Abstract
The present paper is an update of the data on the effects of diseases and environmental factors on the expression and/or activity of human cytochrome P450 (CYP) enzymes and transporters. The data are presented in tabular form (Tables 1 and 2) and are a continuation of previously published summaries on the effects of drugs and other chemicals on CYP enzymes. The collected information presented here is as stated by the cited author(s), and in cases when several references are cited the latest published information is included. Inconsistent results and conclusions obtained by different authors are highlighted, followed by discussion of the major findings. The searchable database is available as an Excel file, for information about file availability contact the corresponding author.
Keywords: Cytochrome P450s, CYPs, transporters, physiological conditions, illness, environmental condition, demographic factors, expression, activity
Introduction
Cytochrome P450 (CYP) enzymes catalyze a number of metabolic reactions that have profound effects on the biological activities (therapeutic and/or toxic) of xenobiotics, including drugs, and the significance of the human enzymes for drug metabolism has been reviewed before [1-3] and updated in the “Update Information on Drug Metabolism Systems—2009, Part I” [4]. The roles of the transporters which, depending on the site of expression, may enhance or limit absorption or excretion of drugs/chemicals from an organ or tissue and have additional effects on the biological activities of drugs/xenobiotics, are reviewed elsewhere [5,6] and updated in Part I [4]. In addition to a great number of xenobiotics influencing the activity and/or expression of the CYP enzymes and transporters, the effects of diseases and environmental factors are also of interest. These factors can have profound effects on the activity and expression and therefore also the final biological activity, efficacy and safety of drugs and other chemicals (Tables 1 and 2). A great number of examples from the literature show that the final effect of a drug/chemical on an organism, whether pharmacological and/or toxicological, depends on regulation of expression and the activity of CYP enzymes and transporters. When these properties are changed by illness or environmental factors, a significant change (e.g. of therapeutic outcome of a drug) might occur. This is of particular interest when diseases such are cancer are considered.
Table 1.
CYP | Categ ory |
Subcate gory |
Effectors | Model | Method | Effect | Remarks | Referen ces |
---|---|---|---|---|---|---|---|---|
CYP1A | Illness | Cancer | Bone carcinoma |
clinical osteosarcoma biopsies samples of primary tumors |
immunohistoch emistry |
expressed in tumor tissue |
[285] | |
CYP1A | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, normal colon, colonic adenoma, and colon carcinoma biopsies |
immunohistoch emistry |
expressed in tumor, not expressed in normal tissue |
suggested as specific marker of colonic neoplasia |
[263,270 ,296] |
CYP1A | Illness | Cancer | Esophagea 1 carcinoma |
esophageal squamous- cell carcinoma, SCC, adenocarcinoma, clinical samples, microsomes from human esophagus with and without tumor tissue |
immunoblotting, immunohistoch emistry |
increase of protein level in tumor tissue compared to samples without tumor, also not present in non- neoplastic samples |
[274,275 ,296] |
|
CYP1A | Illness | Cancer | Gastric carcinoma |
clinical tumor and normal tissue samples |
immunoblotting | expressed in tumor, not expressed in normal stomach tissue |
[276] | |
CYP1A | Illness | Cancer | Leukemia | L1210 leukemia cell lines |
immunoblotting | expressed in sensitive and BCNU resistant lines |
[279] | |
CYP1A | Illness | Cancer | Liver carcinoma |
clinical tumor and normal liver tissue samples, hepatocellular carcinomas (HCC) |
immunohistoch emistry |
variable expression of protein in primary malignant liver tumors |
[273] | |
CYP1A | Illness | Cancer | Prostate carcinoma |
clinical prostate tissue samples |
immunoblotting | expression of protein in prostate epithelium and in prostate tumor cells |
[277,296] | |
CYP1A | Illness | Cancer | Soft tissue carcinoma |
soft tissue sarcomas, clinical samples |
immunoblotting | expression of mRNA in tumor and control tissues |
[284] | |
CYP1A | Food | Dietary habit |
Char grilled meat diet |
small intestine specimens, enzyme activity |
RT-PCR, Western immunoblotting , hepatic enzyme activity |
increase of mRNA and protein expression in liver and small intestine |
[305] | |
CYP1A1 | Illness | Cancer | Brain carcinoma |
medulloblastoma UW228-3 cell line, microsomal proteins |
Western immunoblotting, immunohistoch emistry, RT- PCR, 7- Ethoxyresorufin de-ethylation O- |
not expressed in untreated cells, expressed in Resveratrol and beta-NF treated cells |
[256,300 ,301] |
|
CYP1A1 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples, immortalized non-tumor- and tumor- derived cell lines, T47D and MDA-MB- 231 cells |
RT-PCR, Western immunoblotting immunohistoch emistry, Northern blotting |
Inconsistent results reported - mRNA and protein present in tumor and normal tissues samples, decrease of mRNA expression in tumor as compared with morphologically normal adjacent tissues samples, higher amplification occurred in normal tissues of same individuals, very low level of mRNA in both tumor and normal tissues samples, also protein not expressed, in cells present only after induction with an AhR agonist |
no consistent associations between breast cancer and CYP1A1 polymorphis ms were found, absence of a major association of CYP1A1 with breast cancer |
[34,40,66,69,70, 245,246, 250,251, 296,310, 425] |
CYP1A1 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples | enzyme activity assay |
activity present in tumor tissue |
Conflicting results reported on association of colorectal cancer with CYP1A1 polymorphis m |
[296,425] |
CYP1A1 | Illness | Cancer | Esophagea l carcinoma |
esophagectomy specimens, Barrett’s esophagus, esophageal squamous mucosa, and normal tissue |
RT-PCR | expression of mRNA in tumor tissue, weak expression of mRNA in some normal tissues |
significant, although weak, association of the CYP1A1*2 C allele with esophageal cancer in smokers |
[307,425] |
CYP1A1 | Illness | Cancer | Lung carcinoma |
non-small cell lung cancer tissue, tumor and no tumor lung tissue samples, A549 adenocarcinoma cell line, bronchioloalveolar carcinomas |
RT-PCR, Northern hybridization, Western immunoblotting, immunohistoch emistry |
expression of mRNA and protein, lower expression of CYP1A protein in tumors |
proposed as markers for the determination of quality of lung cancer, neither CYP1A1 Mspl nor CYP1A1 Ile462Val was associated with lung cancer susceptibilit y, secondary role of CYP1A1 polymorphis m and lung cancer risk proposed |
[37,38,39,263,267,282,289,296,337,389,425] |
CYP1A1 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in tumor and control tissues |
[41] | |
CYP1A1 | Illness | Cancer | Prostate carcinoma |
clinical prostate and normal tissues samples |
RT-PCR | expression of mRNA in tumor tissue, benign prostatic hyperplasia (BPH), in prostate cancer cell lines, and normal tissues |
weak association of CYP1A1*2 C alleles with increased risk reported |
[291,387 ,425] |
CYP1A1 | Enviro nment al conditi on |
Cellular osmolality |
Hypertoni c environme nt |
human primary hepatocytes in hypertonic media |
cDNA microarray and RT-PCR |
increase of mRNA expression |
[43] | |
CYP1A1 | Enviro nment al conditi on |
Cigarett e smoke exposur e |
Cigarette smoke |
lung tissue samples, bronchial epithelial cells, adenocarcinoma, bronchoalveolar cancer |
RT-PCR, immunohistoch emistry, immunoblotting |
increase of mRNA and protein expression, and activity in lung of smokers, not expressed in non- smokers |
pulmonary expression appears to be associated with lung cancer risk, no clear association between polymorphis m and enzyme inducibility |
[11,39,308,309,333,334,335,336,389,425] |
CYP1A1 | Enviro nment al conditi on |
Oxidativ e stress |
Reactive oxygen species, hydrogen peroxide |
human hepatoma cell line HepG2, transfected |
Northern blotting, Western immunoblotting |
decrease of mRNA expression, decrease of induced mRNA expression |
intracellular H2O2 released during the catalytic cycle |
[46,47,48,49] |
CYP1A1 | Physio logical conditi on |
Stress | Shear stress |
human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs) |
RT-PCR, Western immunoblotting , Northern blotting |
increase of mRNA, protein expression and activity, mRNA expressed and protein not detected under static conditions |
[388,390] | |
CYP1A2 | Demo graphi c factor |
Age | Adults, aged 18– 46 (median 27) years |
blood samples, human liver microsomes (HLM) |
Alosetron pharmacokineti cs, 7- Ethoxyresorufin de-ethylation O- in HLM |
decrease of metabolic clearance ratio with age, decrease or no statistical difference in activity as a function of age in HLM |
[10,11] | |
CYP1A2 | Demo graphi c factor |
Age | Children under three years old |
clinical urine samples | Theophylline metabolites urinary ratios |
decrease of activity |
[238] | |
CYP1A2 | Illness | Cancer | Esophagea 1 carcinoma |
Esophagectomy specimens, Barrett’s esophagus, esophageal squamous mucosa, and normal tissue |
Western immunoblotting, immunohistoch emistry, RT- PCR |
expression of mRNA and protein |
[307] | |
CYP1A2 | Illness | Cancer | Prostate carcinoma |
clinical prostate and normal tissues samples |
RT-PCR | expression of mRNA in tumor tissue, benign prostatic hyperplasia (BPH), in prostate cancer cell lines, and normal tissues |
[291,292 ,296,387] | |
CYP1A2 | Illness | Cancer | Testicular carcinoma |
urine samples | Caffeine metabolic ratio (AFMU, 1X , 1 U)/17 U |
decrease of activity |
[55] | |
CYP1A2 | Enviro nment al conditi on |
Cellular osmolali ty |
Hypertoni c environme nt |
human primary hepatocytes in hypertonic media |
cDNA microarray and RT-PCR |
decrease of mRNA expression |
[43] | |
CYP1A2 | Enviro nment al conditi on |
Cigarett e smoke exposur e |
Cigarette smoke |
human liver samples, human liver microsomes (HLM), urine samples |
Western immunoblotting, immunohistoch emistry, 7- Ethoxyresorufin de-ethylation O-, Caffeine metabolic ratio (AFMU, 1X , 1 U)/17 U, |
increase of expression and activity in liver of smokers |
positive correlation was found with liver CYP1A2 protein |
[7,8,12,13,309,333] |
CYP1A2 | Therap eutic conditi on |
Contrac eptives |
Contracep tives |
urine samples | Caffeine metabolic ratio (AFMU, 1× , 1 U)/17 U |
decrease of activity |
[12,13] | |
CYP1A2 | Food | Dietary habit |
Broccoli | urine samples | Caffeine metabolic ratio (AFMU, 1× , 1 U)/17 U |
increase of activity |
[12,232] | |
CYP1A2 | Food | Dietary habit |
Kwashior kor, malnutriti on |
African population, children, plasma samples |
Caffeine metabolic index |
decrease of activity, Paraxanthine Cmax and Paraxanthine/Caff eine plasma ratio was significantly lower in kwashiorkor patients than in healthy control |
[223] | |
CYP1A2 | Demo graphi c factor |
Ethnicity | Hispanic | human liver microsomes (HLM) |
7- Ethoxyresorufin de-ethylation O- |
decrease of activity, half of the average activity of those from Caucasians and African Americans |
[11] | |
CYP1A2 | Physio logical conditi on |
Exercise | Physical exercise |
urine samples | Caffeine metabolic ratio (AFMU, 1× , 1 U)/17 U |
increase of activity |
[12] | |
CYP1A2 | Demo graphi c factor |
Gender | Male, Female |
blood samples, human liver microsomes (HLM), urine samples |
Alosetron pharmacokineti cs, 7- Ethoxyresorufin de-ethylation O-, Caffeine metabolic ratio (AFMU, 1× , 1 U)/17U |
increase of activity in non- induced males comparing to non-induced females in clinical studies and in HLM |
[10,11,13] | |
CYP1A2 | Illness | Heart failure |
Congestiv e heart failure |
clinical urine samples | Caffeine metabolic index |
decrease of activity |
[240,241] | |
CYP1A2 | Illness | Infectio n |
Influenza virus epidemic | young children | Theophylline metabolism |
decrease of activity |
[235] | |
CYP1A2 | Illness | Infectio n |
Plasmodiu m falciparum malaria |
African population, adults and children, plasma and saliva samples |
Caffeine metabolic index |
decrease of activity, Paraxanthine Cmax and Paraxanthine/Caff eine plasma ratio was significantly lower in malaria patients than in healthy control |
[222,223] | |
CYP1A2 | Illness | Liver disease |
Liver disease, not specified |
liver disease severity was categorized by use of the Child-Pugh score, plasma and urine samples from volunteers |
Caffeine metabolic index |
decrease of activity |
[51] | |
CYP1A2 | Physio logical conditi on |
Pregnan cy |
Pregnancy | saliva samples | Caffeine metabolic ratio (AFMU, 1× , 1 U)/17 U, Caffeine clearance |
decrease of activity |
[12,53] | |
CYP1A2 | Medici ne |
Vaccine | Virus vaccination |
clinical urine samples | Theophylline clearance |
decrease of activity |
clearance depression after vaccination |
[239] |
CYP1B1 | Illness | Cancer | Bladder carcinoma |
clinical tumor and normal tissue samples, transitional cell carcinoma |
immunoblotting, immunohistoch emistry |
expressed in tumor tissue, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Illness | Cancer | Bone carcinoma |
clinical osteosarcoma biopsies samples of primary tumors |
immunohistoch emistry |
expressed in tumor tissue |
high expression frequency found |
[285] |
CYP1B1 | Illness | Cancer | Brain carcinoma |
clinical tissue samples, glial cell tumors, astrocytoma, medulloblastoma UW228-3 cell line, microsomal proteins |
Western immunoblotting, immunohistoch emistry, RT- PCR, 7- Ethoxyresorufin de-ethylation O- |
expressed in tumor tissue, not expressed in normal tissue |
increased CYP1B1 expression in glial tumors was associated with decreased patient survival time, suggested as prognostic biomarker of human medulloblas tomas, DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[244,249 ,256,257 ,296,300 ,301] |
CYP1B1 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples, immortalized non-tumor- and tumor- derived cell lines, T47D and MDA-MB- 231 cells |
RT-PCR, Western immunoblotting, immunohistoch emistry, Northern blotting |
Inconsistent results reported - mRNA and protein present in tumor and in adjacent normal tissues samples, high overexpression in tumor cells, also no qualitative differences in expression at mRNA level between tumor and surrounding normal tissues samples, lower expression in tumor than in adjacent no tumor tissues samples, also no or very low expression in normal tissue and cells and protein not detectable in normal tissues samples |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy, presence of CYP1B1 in cells decreases their sensitivity to the cytotoxic effects of a specific anticancer drug, no clea association between breast cancer and CYP1B1 polymorphism |
[34,35,40,69,70,75,246,249 ,250,251,257,258,263,296,425] |
CYP1B1 | Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples, adenocarcinoma, primary colorectal cancer, lymph node metastasis |
Western immunoblotting, immunohistoch emistry |
Inconsistent results reported - expressed in tumor tissue, not expressed in normal tissue, also expressed at low levels in normal colonic epithelia and in blood vessels within the colon, higher expression in tumor |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy, also expression in colon tumors does not correlate with tumor stage or degree of lymph node invasion |
[249,253 ,255,257 ,263,296 ,339] |
CYP1B1 | Illness | Cancer | Connectiv e tissue carcinoma |
clinical tissue samples, sarcoma |
immunoblotting, immunohistoch emistry |
expressed in tumor tissue, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Illness | Cancer | Esophagea 1 carcinoma |
clinical tissue samples, squamous carcinoma, esophagectomy specimens, Barrett’s esophagus, and normal tissue |
RT-PCR, Western immunoblotting, immunohistoch emistry |
expression of mRNA and protein in tumor tissue, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257 ,296,307] |
CYP1B1 | Illness | Cancer | Gastric carcinoma |
clinical tumor and normal tissue samples, adenocarcinoma |
immunoblotting, immunohistoch emistry |
expressed in tumor tissue, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Illness | Cancer | Kidney carcinoma |
clinical tissue samples, clear cell and transitional cell carcinoma |
immunoblotting, immunohistoch emistry |
expressed in tumor tissue, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Illness | Cancer | Lung carcinoma |
clinical tissue samples, squamous carcinoma, adenocarcinoma, non- small cell lung cancer, tumor and non-tumor lung tissue samples, A549 adenocarcinoma cell line, bronchoalveolar cancer |
RT-PCR, Western immunoblotting, immunohistoch emistry |
increase of mRNA and protein expression in tumor tissue, expressed in microsomes and cytoplasm of smooth muscle cells, not expressed in pneumocytes of normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed as widely applicable cancer immunotherapy, overexpressi on considered to be aggressive biomarker for non- small cell lung cancer, CYP1B1 Leu432Val was associated with lung cancer susceptibilit y, CYP1B1 expression was not dependent on cigarette smoking in lung adenocarcin oma |
[249,257 ,282,283 ,289,296 ,337,389] |
CYP1B1 | Illness | Cancer | Lymphoid carcinoma |
clinical tissue samples, non-Hodgkin’s lymphoma |
immunoblotting, immunohistoch emistry |
expressed in tumor tissue, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues, higher expression in NPC tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[41,257] |
CYP1B1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, adenocarcinoma, primary epithelial ovarian cancer, primary and metastatic ovarian cancer |
immunoblotting, immunohistoch emistry |
highly expressed in primary tumor tissue, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy, positive correlation with prostate cancer risk reported |
[249,252 ,257,260 ,425] |
CYP1B1 | Illness | Cancer | Prostate carcinoma |
clinical prostate tissue samples and prostate cancer cell lines |
RT-PCR, Western immunoblotting, immunohistoch emistry |
increase of expression of mRNA and protein comparing to control tissue samples, present in benign prostatic hyperplasia (BPH), and normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy, positive association with prostate cancer risk reported |
[68,257, 291,292, 296,387, 425] |
CYP1B1 | Illness | Cancer | Skin carcinoma |
clinical tissue samples, squamous carcinoma |
immunoblotting, immunohistoch emistry |
expressed in tumor, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Illness | Cancer | Testicular carcinoma |
clinical tissue samples, malignant germ cell tumor |
immunoblotting, immunohistoch emistry |
expressed in tumor, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Illness | Cancer | Uterus carcinoma |
clinical tissue samples, adenocarcinoma, malignant mixed Mullerian tumor |
immunoblotting, immunohistoch emistry |
expressed in tumor, not expressed in normal tissue |
DNA-based vector encoding CYP1B1 DNA proposed for widely applicable cancer immunother apy |
[249,257] |
CYP1B1 | Enviro nment al conditi on |
Cigarett e smoke exposur e |
Cigarette smoke |
lung tissue samples, bronchial epithelial cells, bronchoalveolar cancer |
RT-PCR, immunohistoch emistry, immunoblotting |
increase of expression of mRNA and protein in smokers |
[11,309, 335,336, 389] |
|
CYP1B1 | Physio logical conditi on |
Stress | Shear stress |
human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs) |
RT-PCR, Western immunoblotting , Northern blotting |
increase of mRNA, protein expression and activity, mRNA and protein expressed under static conditions |
[388,390] | |
CYP2A,2B | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian tissue |
immunoblotting, immunohistoch emistry |
increase of expression in primary tumor tissue comparing to normal tissue, high expression in metastatic ovarian tissue |
negative or low or moderate expression compared to high expression associated with poor survival |
[252] |
CYP2A,2B | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer, lymph node metastasis |
immunoblotting, immunohistoch emistry |
low expression in tumor tissue |
correlation between expression in primary tumors and correspondi ng lymph node metastases |
[253] |
CYP2A6 | Demo graphi c factor |
Age | Adults aged less then 20 till over 60 years |
human liver microsomes (HLM) |
Coumarin hydroxylation C7- |
increase of activity with age |
[11] | |
CYP2A6 | Enviro nment al conditi on |
Cadmiu m exposur e |
Cadmium | urine samples | 7- Hydroxycoumar in, Umbelliferone urine excretion |
increase of activity in men and women, increase of expression proposed |
[25,26,27] | |
CYP2A6 | Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples, breast reduction sample microsomes |
RT-PCR, Western immunoblotting |
mRNA not present in tumor and normal tissues samples, mRNA, protein and activity detected in reduction samples |
[69,70] | |
CYP2A6 | Illness | Cancer | Colorectal carcinoma |
clinical tumor tissue samples, adenoma, adenocarcinoma and adjacent mucosa |
immunohistoch emistry, in situ hybridization |
increased expression of mRNA and protein in adenocarcinoma, very low or no protein detected in normal mucosa |
suggested that may have important roles in human colorectal tumorigenes is and progression, risk for colorectal cancer increased in parallel with CYP2A6 enzyme activity. |
[69,70,407,420] |
CYP2A6 | Illness | Cancer | Lung carcinoma |
clinical tumor tissue samples, non-small cell lung cancer tissue, squamous cell carcinoma, lung adenocarcinoma |
RT-PCR, Northern blotting, immunohistoch emistry, in situ hybridization (ISH) |
expression of mRNA and protein |
proposed as markers for the determinatio n of quality of lung cancer, no association was observed between CYP2A6 genotype and risk of lung cancer |
[37,237, 413] |
CYP2A6 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP2A6 | Illness | Cancer | Prostate carcinoma |
clinical prostate and normal tissues samples |
RT-PCR | expression of mRNA in tumor and normal tissues |
[306] | |
CYP2A6 | Demo graphi c factor |
Ethnicit y |
Hispanic | human liver microsomes (HLM) |
Coumarin hydroxylation C7- |
increase of activity, twice of the average activity of those from Caucasians and African Americans |
[11] | |
CYP2A6 | Enviro nment al conditi on |
Lead exposur e |
Lead | urine samples | 7- Hydroxycoumar in, Umbelliferone urine excretion |
decrease of activity in men due to decrease of expression proposed, not observed in women |
[26,27] | |
CYP2A6 | Illness | Liver disease |
Alcoholic liver disease (ALD) |
liver biopsy samples | immunohistoch emistry, Western immunoblotting |
increase of protein level |
[225] | |
CYP2A6 | Illness | Liver disease |
Steatosis, nonalcoho lic fatty liver (NAFL) |
liver biopsy samples | immunohistoch emistry, Western immunoblotting |
increase of protein level |
[225] | |
CYP2A7 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissue samples |
RT-PCR | mRNA not present in tumor and normal tissue samples |
[69] | |
CYP2A13 | Illness | Cancer | Breast carcinoma |
clinical samples, breast tissue and tumors |
RT-PCR | mRNA not present in tumor and normal tissues samples |
[69] | |
CYP2A13 | Illness | Cancer | Lung carcinoma |
lung adenocarcinoma tissue, normal tissue and tissue lung carcinoma samples |
RT-PCR, immunohistoch emistry, immunoblotting |
expression of mRNA in tumor tissue, low or no expression of protein in tumor tissue, expressed in the epithelial cells of human bronchus and trachea of normal tissue |
high efficiency in the metabolic activation of tobacco carcinogen NNK, CYP2A13 genotype is associated with reduced risk of lung adenocarcin oma |
[237,259] |
CYP2A13 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP2B6 | Demo graphi c factor |
Age | Adults aged less then 20 to over 60 years |
human liver microsomes (HLM) |
Mephenytoin (S)- demethylation N- (Nirvanol formation) |
decrease of activity with age |
[11] | |
CYP2B6 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples |
RT-PCR, Western immunoblotting |
Inconsistent results reported - decrease of protein expression in tumor as compared with morphologically normal adjacent tissues samples, also no qualitative differences in expression at mRNA level between tumor and surrounding normal tissues |
[66,69,70] | |
CYP2B6 | Illness | Cancer | Esophagea l carcinoma |
esophageal squamous- cell carcinoma, SCC, clinical samples, microsomes from human esophagus with and without tumorous tissue |
immunoblotting | expression of protein in tumor tissue |
[275] | |
CYP2B6 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP2B6 | Demo graphi c factor |
Ethnicity | Hispanic | human liver microsomes (HLM) |
Mephenytoin (S)- demethylation N- (Nirvanol formation) |
increase of activity, twice the average activity of those from Caucasians and African Americans |
[11] | |
CYP2B7 | Illness | Cancer | Lung carcinoma |
non-small cell lung cancer tissue samples |
RT-PCR, immunohistoch emistry |
decrease of expression of mRNA in tumor tissue, expressed in normal tissue |
[263,264 ,296] |
|
CYP2C | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples |
RT-PCR, Western immunoblotting, immunohistoch emistry |
very low expression, mRNA and protein present in tumor and normal tissues samples, no qualitative differences in expression of mRNA between tumor and surrounding normal tissue |
[35,69,70,296,310] | |
CYP2C | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer, lymph node metastasis |
immunoblotting, immunohistoch emistry |
low expression in tumor tissue |
correlation between expression in primary tumors and correspondi ng lymph node metastases |
[253] |
CYP2C | Illness | Cancer | Esophagea l carcinoma |
esophageal squamous- cell carcinoma, SCC, carcinoma endoscopy tissue samples, esophagectomy specimens, Barrett’s esophagus, esophageal squamous mucosa |
RT-PCR | expression of mRNA and protein in tumor and normal tissue, expression of mRNA significantly lower in tumor tissue |
[31,307] | |
CYP2C | Illness | Cancer | Lung carcinoma |
A549 adenocarcinoma cell line |
Northern blotting, RT- PCR, immunohystoch emistry |
expression of mRNA in tumor cells, protein expressed in normal cells |
[296,337] | |
CYP2C | Illness | Cancer | Prostate carcinoma |
clinical prostate tissue samples |
immunoblotting, immunohistoch emistry |
expression of protein in prostate epithelium and in prostate tumor cells |
[277,296] | |
CYP2C | Illness | Cancer | Silvary gland carcinoma |
clinical samples, pleomorphic adenoma |
immunoblotting, immunohistoch emistry |
expression of protein |
[324] | |
CYP2C8 | Demo graphi c factor |
Age | Adults aged less then 20 till over 60 years |
human liver microsomes (HLM) |
Placitaxel hydroxylation C6alpha- |
no statistically significant difference of activity with age |
[11] | |
CYP2C8 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples, microsomes |
RT-PCR, Western immunoblotting |
very low expression |
[35,40,67] | |
CYP2C8 | Illness | Cancer | Colorectal carcinoma |
normal tissue and adenomatous colonic tissue endoscopy samples, Human colorectal cancer cells (Caco-2) |
RT-PCR, Western immunoblotting , 6alpha- i 3′-p- paclitaxel hydroxylation |
expression of CYP mRNA similar among adenomatous colonic and normal tissues, decrease of protein level in normal tissue of patients with adenomas comparing to biopsies obtained from disease-free controls |
[65,423] | |
CYP2C8 | Illness | Cancer | Esophagea l carcinoma |
esophageal squamous- cell carcinoma, SCC, carcinoma endoscopy tissue samples |
Western immunoblotting |
increase of protein level in normal tissue of esophageal SCC patients compared to controls |
[31] | |
CYP2C8 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP2C8 | Demo graphi c factor |
Ethnicity | Hispanic | human liver microsomes (HLM) |
Hydroxylation C6alpha- (taxane ring) |
increase of activity, twice the average activity of those from Caucasians and African Americans |
[11] | |
CYP2C8 | Physio logical conditi on |
Hypoxia | Decreased oxygen pressure |
human umbilical vein endothelial cells (HUVECs) |
RT-PCR, Western immunoblotting , RT-PCR, 11,12-EET and 11,12-Dihydroxyeicos atrienoic acid (11,12-DHET) formation |
increase of mRNA expression, protein level, and activity |
[56] | |
CYP2C8,1
9 |
Enviro nment al conditi on |
Cadmiu m exposur e |
Cadmium | human liver samples, human liver microsomes (HLM) |
Western immunoblotting , liver histopathology |
decrease of protein levels associated with liver pathology after Cd exposure in vivo |
[7] | |
CYP2C9 | Demo graphi c factor |
Age | Adults aged less then 20 till over 60 years |
human liver microsomes (HLM) |
Diclofenac hydroxylation C4′- |
no statistically significant difference of activity with age |
[11] | |
CYP2C9 | Physio logical conditi on |
Ambient osmolali ty |
Hypertoni c environme nt |
human primary hepatocytes in hypertonic media |
RT-PCR | no change in mRNA expression reported |
[43] | |
CYP2C9 | Enviro nment al conditi on |
Cadmiu m exposur e |
Cadmium | human liver samples, human liver microsomes (HLM) |
Western immunoblotting |
elevated levels of protein associated with cadmium accumulation |
[7] | |
CYP2C9 | Illness | Cancer | Brain carcinoma |
clinical tissue samples, glioma, ependymoma, lymphoma-metastases |
RT-PCR, immunohistoch emistry |
expressed in tumor and normal tissues |
[296,299] | |
CYP2C9 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples, microsomes |
RT-PCR, Western immunoblotting |
very low expression |
[35,40,67] | |
CYP2C9 | Illness | Cancer | Carcinom a, not specified |
plasma and urine samples |
Tolbutamide urine metabolite ratios, oral clearance |
no difference in activity in people with and without cancer |
[229] | |
CYP2C9 | Illness | Cancer | Colorectal carcinoma |
healthy vountiers and tumor colonic tissue endoscopy biopsies and/or surgical resection samples |
RT-PCR and restriction mapping |
expression of CYP mRNA in both tumorand normal tissues |
Inconsitent results obtained on polymorphis m as a risk factors |
[426] |
CYP2C9 | Illness | Cancer | Esophagea l carcinoma |
esophagectomy specimens, esophageal squamous-cell carcinoma, SCC, adenocarcinoma, Barrett’s esophagus, esophageal squamous mucosa, and normal tissue |
RT-PCR, Western immunoblotting, immunohistoch emistry |
expression of mRNA and protein in tumor tissue, not expressed in normal tissue samples |
[274,307] | |
CYP2C9 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP2C9 | Demo graphi c factor |
Ethnicity | Japanese | blood samples, unbound oral clearance |
genotyping, Warfarin (S)- unbound concentrations, Warfarin (S)- C7-hydroxy urinary excretion rates |
genotype dependent unbound oral clearance in Japanese, gene- dose effect of defective CYP2C9 alleles on the in vivo CYP2C9 activity is evident in Japanese patients but not in Caucasian patients |
[230] | |
CYP2C9 | Physio logical conditi on |
Hypoxia | Decreased oxygen pressure |
human umbilical vein endothelial cells (HUVECs) |
RT-PCR, Western immunoblotting , RT-PCR, 11,12-EET and 11,12- Dihydroxyeicos atrienoic acid (11,12- DHET) formation |
increase of mRNA expression, protein level, and activity |
[56] | |
CYP2C19 | Demo graphi c factor |
Age | Adults aged less then 20 to over 60 years |
human liver microsomes (HLM) |
Mephenytoin (S)- hydroxylation C4′- |
decrease of activity with age |
[11] | |
CYP2C19 | Illness | Cancer | Advanced metastatic cancer |
blood samples | Omeprazole C5-pyridinyl methyl hydroxylation index |
decrease of activity |
[241,242] | |
CYP2C19 | Illness | Cancer | Hepatic carcinoma |
clinical cancer tissue samples, hepatocarcinoma cell lines |
RT-PCR, Western immunoblotting |
expression of protein in tumor and normal tissues, increase of expression of mRNA in tumor comparing to normal tissues |
[298] | |
CYP2C19 | Illness | Cancer | Prostate carcinoma |
clinical prostate and normal tissues samples |
RT-PCR | expression of mRNA in tumor and normal tissues |
no association of the CYP2C19* 2 allele and prostate cancer observed |
[291,292 ,296,425] |
CYP2C19 | Therap eutic conditi on |
Contrac eptives |
Contracep tives |
urine samples | Mephenytoin (S)-hydroxylation C4′-, the S/R- ratio , |
decrease of activity in females |
[23] | |
CYP2C19 | Demo graphi c factor |
Ethnicity | Oriental extensive metaboliz ers (EMs) |
blood samples, oral clearance |
Omeprazole hydroxylation C5-pyridinyl methyl |
decrease of clearance comparing to Caucasian EMs |
[21] | |
CYP2C19 | Demo graphi c factor |
Gender | Male, Female |
human liver microsomes (HLM), urine and blood samples, |
Mephenytoin (S)- hydroxylation C4′-, ratio of micromoles of (S)- Mephenytoin dose to micromoles of 4′-OH-M excreted in urine and the S/R-ratio |
Inconsistent results reported - increase of activity in females, other results show opposite or no differences |
[11,22] | |
CYP2C19 | Illness | Heart failure |
Congestiv e heart failure |
clinical blood and urine samples |
Mephenytoin metabolism |
decrease of activity |
[240,241] | |
CYP2C19 | Illness | Liver disease |
Liver disease, not specified |
liver disease severity was categorized by use of the Child-Pugh score, plasma and urine samples from volunteers |
Mephenytoin metabolic index and disposition |
decrease of activity, decrease of plasma clearance |
[51,52] | |
CYP2D6 | Demo graphi c factor |
Age | Adults | human liver microsomes (HLM), hepatocytes, |
Dextromethorp han demethylation N- |
decrease of activity with age in HLM, no significant differences in hepatocytes |
[11] | |
CYP2D6 | Illness | Cancer | Bladder carcinoma |
clinical tumor and normal tissue samples, human bladder microsomes |
RT-PCR, Western immunoblotting, immunochemist ry |
expression of mRNA in tumor tissue |
[304] | |
CYP2D6 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples |
RT-PCR, Western immunoblotting |
Inconsistent results reported - mRNA and protein present in tumor and normal tissues samples, no qualitative differences at mRNA level between tumor and surrounding normal tissue samples, also no expression reported |
[34,40,69, 70] |
|
CYP2D6 | Illness | Cancer | Lung carcinoma |
clinical samples, tumor and normal tissue samples |
RT-PCR, immunohistoch emistry |
very low or no expression of mRNA or protein in tumor and normal tissue |
modest associationo f polymorphis m as a risk factor |
[281,425] |
CYP2D6 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41 | |
CYP2D6 | Illness | Cancer | Prostate carcinoma |
clinical prostate and normal tissues samples |
RT-PCR, Dextromethorp han demethylation N- |
expression of mRNA and activity in tumor and normal tissues |
[291,292 ,295,296] | |
CYP2D6 | Enviro nment al conditi on |
Cellular osmolali ty |
Hypertoni c environme nt |
human primary hepatocytes in hypertonic media |
cDNA microarray and RT-PCR |
decrease of mRNA expression |
[43] | |
CYP2D6 | Demo graphi c factor |
Ethnicit y |
Black extensive metaboliz ers (EMs) |
blood samples, oral clearance |
Debrisoquine/S parteine hydroxylation |
decrease of mean activity comparing to Caucasian EMs |
[20] | |
CYP2D6 | Demo graphi c factor |
Ethnicit y |
Oriental extensive metaboliz ers (EMs) |
blood samples, oral clearance |
Debrisoquine/S parteine hydroxylation |
decrease of mean activity comparing to Caucasian EMs |
[20] | |
CYP2D6 | Demo graphi c factor |
Gender | Male, Female |
human liver microsomes (HLM) |
Dextromethorp han demethylation N- |
no significant difference in activity or higher activity in male HLM, decrease of activity when investigated as ratio in vivo in EMs |
[11] | |
CYP2D6 | Illness | Infectio n |
Human immunode ficiency virus, HIV, positive patients |
blood samples | Dextromethorp han demethylation N-, RT-PCR |
changes may occur in HIV- positive patients such that their CYP2D6 activity approaches that of PMs, despite having an EM genotype |
[221] | |
CYP2D6 | Illness | Liver disease |
Liver disease, not specified |
liver disease severity was categorized by use of the Child-Pugh score, plasma and urine samples from volunteers |
Debrisoquine metabolic index and disposition |
decrease of recovery ratio, no effect on disposition |
[51,52] | |
CYP2D6 | Physio logical conditi on |
Pregnancy | Pregnancy | urine samples | Dextromethorp han/Dextrorpha n urinary ratio |
increase of activity in EM |
[53,54] | |
CYP2E1 | Demo graphi c factor |
Age | Adults aged less then 20 to over 60 years |
human liver samples, human liver microsomes (HLM), hepatocytes |
protein level determination, Chlorzoxazone hydroxylation C6- |
decrease of activity in HLM, negative association between age and protein content, no significant differences in activity in hepatocytes |
[8,11,16] | |
CYP2E1 | Enviro nment al conditi on |
Cadmiu m exposur e |
Cadmium | liver autopsy samples, human liver microsomes (HLM) |
Western immunoblotting |
increase of protein expression with increased Cd accumulation |
[28] | |
CYP2E1 | Illness | Cancer | Brain carcinoma |
clinical tissue samples, glioma, acoustic neuroma |
RT-PCR, immunohistoch emistry |
expressed in tumor and normal tissue samples |
[296,300] | |
CYP2E1 | Illness | Cancer | Breast carcinoma |
tumor and normal tissue samples, clinical samples |
RT-PCR, Western immunoblotting, immunohistoch emistry |
Inconsistent results reported- expression of mRNA and protein in tumor and normal tissue samples with no qualitative differences, increase of expression with an invasive lobular type of tumor, also no expression, or decrease of protein expression in tumor tissue as compared with morphologically normal adjacent tissue reported |
potential role as a breast cancer prognosis marker suggested |
[35,40,66, 69,70, 296] |
CYP2E1 | Illness | Cancer | Colorectal carcinoma |
normal tissue and adenomatous colonic tissue endoscopy samples |
RT-PCR, Western immunoblotting |
expression of CYP mRNA was similar among normal and adenomatous colonic tissues |
[65] | |
CYP2E1 | Illness | Cancer | Esophagea l carcinoma |
esophageal squamous- cell carcinoma, SCC, carcinoma endoscopy tissue samples, esophagectomy specimens, Barrett′s esophagus, esophageal squamous mucosa |
RT-PCR, Western immunoblotting, immunohistoch emistry |
expression of mRNA and protein in tumor and in normal tissue, expression of protein was significantly lower in control tissue |
[31,307] | |
CYP2E1 | Illness | Cancer | Lung carcinoma |
non-small cell lung cancer tissue, primary pulmonary adenocarcinomas and squamous cell carcinoma and surrounding normal bronchial tissue, A549 adenocarcinoma cell line |
RT-PCR, immunohistoch emistry, Northern blotting |
mRNA expression in adenocarcinoma, protein expressed in tumor and normal bronchial tissue, mRNA expressed in tumor cells |
proposed as marker for the determinatio n of quality of lung cancer |
[37,280, 296,309, 332,337] |
CYP2E1 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non cancerous nasopharynx tissues |
[41] | |
CYP2E1 | Enviro nment al conditi on |
Cellular osmolality |
Hypertoni c environme nt |
human primary hepatocytes in hypertonic media |
cDNA microarray and RT-PCR, Nitrophenol hydroxylation |
increase of mRNA expression, protein level and activity |
[43] | |
CYP2E1 | Illness | Diabetes | Diabetes, type I |
blood plasma samples, urine samples, peripheral blood mononuclear cells |
Chlorzoxazone hydroxylation C6-, AUC, RT- PCR |
increase of mRNA expression, no difference in oral clearance |
[60] | |
CYP2E1 | Illness | Diabetes | Diabetes, type II |
blood plasma samples, urine samples, peripheral blood mononuclear cells |
Chlorzoxazone hydroxylation C6-, AUC, RT- PCR |
increase of mRNA expression and activity, increase of oral clearance |
[6,59] | |
CYP2E1 | Food | Dietary habit |
Fasting, Dietary sugar restriction |
blood plasma samples | Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio, AUC |
decrease of oral clearance and lower hydroxylation activity |
[14,19] | |
CYP2E1 | Food | Dietary habit |
High dietary sugar |
blood plasma samples | Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio, AUC |
decrease of activity |
[14] | |
CYP2E1 | Food | Dietary habit |
Moderate alcohol consumpti on |
serum samples, peripheral lymphocytes |
Chlorzoxazone oral clearance, RT-PCR |
Chlorzoxazone clearance was significantly higher in alcoholics than in nonalcoholic, mRNA levels were not significantly different between the groups |
clinically significant interaction potential - no correlation was observed between lymphocyte CYP mRNA and in vivo CYP activity |
[16,218] |
CYP2E1 | Demo graphi c factor |
Gender | Male, Female |
blood samples, hepatocytes, human liver microsomes (HLM) |
Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio, activity |
decrease of 6- OH/Chlorzoxazon e ratio in women comparing to men, no difference in activity in hepatocytes or HLM |
[10,11] | |
CYP2E1 | Illness | Inflamm ation |
Inflammat ory liver disease |
liver biopsy samples | RT-PCR | decrease of mRNA level |
[294] | |
CYP2E1 | Illness | Liver disease |
Alcoholic liver disease (ALD) |
blood mononuclear cells, blood plasma samples, lymphocyte microsomes, human liver samples |
RT-PCR, Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio, Western immunoblotting immunohistoch emistry, protein level determination |
increase of mRNA expression, protein level, hydroxylation activity and drug clearance in alcoholic healthy subjects, decrease of activity with progression and severity of ALD |
clinically significant drug interaction potential - monitoring CYP2E1 mRNA expression in mononuclea r cells suggested as useful predictor of alcohol- mediated alterations in hepatic activity in heavy alcohol consumptio n, no correlation in moderate alcohol consumptio n |
[6,8,16,215, 216,217, 218,224, 225] |
CYP2E1 | Illness | Liver disease |
Liver disease, not specified |
liver disease severity was categorized by use of the Child-Pugh score, plasma and urine samples from volunteers |
Debrisoquine metabolic index |
decrease of metabolic ratio |
[51] | |
CYP2E1 | Illness | Liver disease |
Nonalcoh olic steatohepa titis (NASH) |
blood plasma samples, liver biopsy samples, human liver microsomes (HLM), peripheral lymphocytes |
Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio, immunohistoch emistry, Western immunoblotting, RT-PCR, Nitrophenol hydroxylation |
increase of mRNA expression protein level and activity, increase of oral clearance |
suggested as reliable indicator of liver injury |
[18,219, 220,224, 226,227, 228,248] |
CYP2E1 | Illness | Liver disease |
Steatosis in chronic hepatitis C |
liver biopsy samples | RT-PCR | increase of mRNA expression |
[213] | |
CYP2E1 | Illness | Liver disease |
Steatosis, nonalcoho lic fatty liver (NAFL) |
blood plasma samples, liver biopsy samples, human liver microsomes (HLM), peripheral lymphocytes |
Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio, immunohistoch emistry, Western immunoblotting , RT-PCR |
Inconsistent results reported - increase of oral clearance, increase of protein level and activity, also no increase in protein level and activity observed, higher levels of mRNA could be observed in the steatotic/normal biopsy samples as compared with the inflammation samples |
[219,220 ,225,226 ,227,228 ,294] |
|
CYP2E1 | Illness | Obesity | Morbid obesity |
blood plasma samples, urine samples |
Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio |
increase of oral clearance and activity |
clinically
significant pharmacok inetic drug- drug interaction potential |
[18,19,59, 215,219, 243] |
CYP2E1 | Enviro nment al conditi on |
Oxidativ e stress |
Reactive oxygen species, hydrogen peroxide |
human hepatoma cell line HepG2, transfected, HepG2 microsomal fraction |
Northern blotting, Western immunoblotting |
decrease of mRNA expression and labilization of protein, repression of ROS-producing system |
intracellular H2O2 production resulting from CYP2E1 activity can repress the expression of CYP1A1, CYP1A1 activity represses the CYP2E1 gene promoter |
[49] |
CYP2E1 | Therap eutic conditi on |
Transpla ntation |
Liver transplant ation |
blood plasma samples | Chlorzoxazone hydroxylation C6-, metabolite/subst rate ratio |
increase of activity in liver of transplant patients |
clinically significant pharmacok inetic drug- drug interaction potential - |
[17] |
CYP2F1 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissue samples |
RT-PCR | mRNA not present in tumor and normal tissue samples |
[69] | |
CYP2F1 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer, lymph node metastasis |
immunoblotting, immunohistoch emistry |
low expression in tumor tissue |
correlation between expression in primary tumors and correspondi ng lymph node metastases |
[253] |
CYP2F1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian cancer |
immunoblotting, immunohistoch emistry |
increase of expression in primary tumor tissue comparing to normal tissue |
[252] | |
CYP2J2 | Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissues samples, cancer cell lines |
immunohistoch emistry, immunoblotting , RT-PCR |
expression of mRNA and protein in tumor tissues and cells not expressed in adjacent normal tissue |
potential biomarker and target for therapy of human cancers |
[338] |
CYP2J2 | Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissues samples, colon adenocarcinoma, cancer cell lines |
immunohistoch emistry, immunoblotting , RT-PCR |
expression of mRNA and protein in tumor tissues and cells not expressed in adjacent normal tissue |
potential biomarker and target for therapy of human cancers |
[338] |
CYP2J2 | Illness | Cancer | Esophagea l carcinoma |
clinical tumor and normal tissues samples, esophageal adenocarcinoma, cancer cell lines |
immunohistoch emistry, immunoblotting , RT-PCR |
expression of mRNA and protein in tumor tissues and cells not expressed in adjacent normal tissue |
potential biomarker and target for therapy of human cancers |
[338] |
CYP2J2 | Illness | Cancer | Gastric carcinoma |
clinical tumor and normal tissue samples, cancer cell lines |
immunohistoch emistry, immunoblotting , RT-PCR |
expression of mRNA and protein in tumor tissues and cells, not expressed in adjacent normal tissue |
potential biomarker and target for therapy of human cancers |
[338] |
CYP2J2 | Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissues samples, cancer cell lines |
immunohistoch emistry, immunoblotting , RT-PCR |
expression of mRNA and protein in tumor tissues and cells not expressed in adjacent normal tissue |
potential biomarker and target for therapy of human cancers |
[338] |
CYP2J2 | Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissues samples, small cell lung cancer tissue samples, pulmonary squamous- cell carcinoma, pulmonary adenocarcinoma, cancer cell lines |
immunohistoch emistry, immunoblotting , RT-PCR |
expression of mRNA and protein in tumor tissues and cells not expressed in adjacent normal tissue |
potential biomarker and target for therapy of human cancers |
[338] |
CYP2J2 | Physio logical conditi on |
Hypoxia | Decreased oxygen pressure |
human hepatoma cell line HepG2, transfected |
RT-PCR, Western immunoblotting |
decrease of mRNA and protein expression |
[57,58] | |
CYP2R1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian cancer |
immunoblotting, immunohistoch emistry |
increase of expression in primary tumor tissue comparing to normal tissue |
[252] | |
CYP2S1 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer, lymph node metastasis |
immunoblotting, immunohistoch emistry |
increase of expression in primary tumor tissue comparing to normal tissue, high expression in normal colon, high expression in metastatic ovarian tissue |
correlation between expression and tumor stage found, high expression associated with poor prognosis |
[253,288] |
CYP2S1 | Illness | Cancer | Lung carcinoma |
clinical tissue samples, squamous cell carcinomas |
immunoblotting, immunohistoch emistry |
Inconsistent results reported - high expression or only weak expression in lung squamous cell carcinomas tumor tissue, in adenocarcinoma expression was undetectable, high expression in the respiratory epithelium of the bronchus normal tissue |
[288] | |
CYP2S1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian tissue |
immunoblotting, immunohistoch emistry |
high expression in primary tumor tissue, no or very low expression in normal tissue, high expression in metastatic ovarian tissue |
[252,288] | |
CYP2S1 | Illness | Cancer | Uterus carcinoma |
clinical tissue samples, squamous cell carcinoma of the uterine cervix |
immunoblotting, immunohistoch emistry |
high expression in the squamous cell carcinoma of the uterine cervix, expressed in normal tissue |
[288] | |
CYP2S1 | Physio logical conditi on |
Hypoxia | Decreased oxygen pressure |
human umbilical vein endothelial cells (HUVECs), human hepatocellular carcinoma cell line HepG2 |
RT-PCR, Western immunoblotting , RT-PCR, 11,12-EET and 11,12- Dihydroxyeicos atrienoic acid (11,12- DHET) formation |
increase of mRNA expression, protein level, and activity |
[56,286] | |
CYP2U1 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer |
immunoblotting, immunohistoch emistry |
increase of expression in tumor comparing to normal tissue |
correlation between expression and tumor stage reported |
[253] |
CYP2U1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian cancer |
immunoblotting immunohistoch emistry |
high increase of expression in primary tumor tissue comparing to normal tissue |
[252] | |
CYP2W1 | Illness | Cancer | Adrenal carcinoma |
tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting | mRNA and protein expressed in tumor samples, not expressed in normal tissue |
[311] | |
CYP2W1 | Illness | Cancer | Bladder carcinoma |
clinical tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting |
low expression of mRNA and protein |
[311] | |
CYP2W1 | Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting |
low expression of mRNA and protein |
[311] | |
CYP2W1 | Illness | Cancer | Colorectal carcinoma |
tumor and normal tissue samples, human colon carcinoma cell lines, immunohistochemistry |
RT-PCR, Northern blotting, Western immunoblotting |
high expression of mRNA and low to high expression of protein in tumor samples, low or no expression in normal tissue |
suggested as an independent prognostic factor for overall survival, high expression was associated with a worse clinical outcome |
[311,312 ,382] |
CYP2W1 | Illness | Cancer | Gastric carcinoma |
clinical tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting |
higher expression in tumor samples then in normal tissue |
[311] | |
CYP2W1 | Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting |
low expression of mRNA and protein |
[311] | |
CYP2W1 | Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting |
expression in tumor samples, not expressed in normal tissue |
[311] | |
CYP2W1 | Illness | Cancer | Pancreatic carcinoma |
clinical tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting |
low expression of mRNA and protein |
[311] | |
CYP2W1 | Illness | Cancer | Thyroid carcinoma |
clinical tumor and normal tissue samples |
RT-PCR, Northern blotting, Western immunoblotting |
low expression of mRNA and protein |
[311] | |
CYP3A | Demo graphi c factor |
Age | Adults, aged 20 to 83 years |
human plasma samples, human liver microsomes (HLM), hepatocytes |
Triazolam pharmacokinetics, Erythromycin demethylation N-, Testosterone hydroxylation C6beta- |
Inconsistent results reported- decrease of clearance with increasing age in men, age had no significant effect on clearance of Triazolam in women, activity unaffected by age reported for Erythromycin N- demethylation, no significant differences in hepatocytes for Testosterone hydroxylation C6beta- |
[8,9,11,15] | |
CYP3A | Illness | Cancer | Bone carcinoma |
clinical osteosarcoma biopsies samples of primary tumors |
immunohistoch emistry |
expressed in tumor tissue, higher expression in primary biopsies of patients who developed distant metastatic disease |
suggested that high expression may predict metastasis and poor prognosis in osteosarcom as |
[285] |
CYP3A | Illness | Cancer | Breast and other carcinoma |
clinical samples, tumor and normal tissue samples, blood samples |
RT-PCR, Erythromycin breath test, Docetaxel or Vinorelbine clearance, immunohistoch emistry |
mRNA present in tumor and normal tissue samples, decrease of activity |
[70,233, 241,291] |
|
CYP3A | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, normal colon, colonic adenoma, and colon carcinoma biopsies, colonal cancer and healthy tissue microsomes |
immunohistoch emistry, Western immunoblotting, immunohistoch emistry, nifedipine oxidase and 3′- P- hydroxypaclitax el activity |
expressed in healthy and tumor samples, low expression in normal tissue samples |
suggested as specific marker of colonic neoplasia |
[263,269 ,270,296 ,424] |
CYP3A | Illness | Cancer | Esophagea l carcinoma |
esophageal squamous- cell carcinoma, SCC, adenocarcinoma, clinical samples |
immunoblotting immunohistoch emistry |
expression of protein in tumor, not expressed in normal tissue samples, MRNA expressed in normal tissue |
[274,275 ,296] |
|
CYP3A | Illness | Cancer | Gastric carcinoma |
clinical stomach tissue samples |
immunoblotting | expressed in tumor, not expressed in normal tissue samples |
[276] | |
CYP3A | Illness | Cancer | Liver carcinoma |
clinical tumor and normal liver tissue samples, hepatocellular carcinomas (HCC) |
immunohistoch emistry |
decreased or variable expression of protein in primary malignant liver tumors compared to normal tissue samples, decrease or no expression in metastasis, decrease of activity |
[271,272 ,273] |
|
CYP3A | Illness | Cancer | Lung carcinoma |
non-small cell lung cancer tissue samples, blood samples |
RT-PCR, Erythromycin breath test, immunohistoch emistry |
expression of mRNA and protein in adenocarcinoma and normal tissue samples, decrease of activity in tumor tissue samples |
proposed as markers for the determinatio n of quality of lung cancer |
[37,233, 263,265, 266,296] |
CYP3A | Illness | Cancer | Prostate carcinoma |
clinical prostate tissue samples |
immunoblotting, Dextromethorp han demethylation O- |
expression of mRNA and activity in tumor and normal tissue samples |
[277,295 ,296] |
|
CYP3A | Illness | Cancer | Soft tissue carcinoma |
soft tissue sarcomas, clinical samples |
immunoblotting | expression of mRNA in tumor and normal tissue samples |
[284] | |
CYP3A | Enviro nment al conditi on |
Cigarett e smoke exposur e |
Cigarette smoke |
lung tissue samples, bronchoalveolar macrophages |
RT-PCR, immunoblotting |
decrease of mRNA and protein in expression of smokers |
high level of CYP3A in smokers or non- smokers associated with DNA- adduct formation |
[336] |
CYP3A | Food | Dietary habit |
Moderate alcohol consumpti on |
clinical samples, serum samples, peripheral lymphocytes, RT-PCR |
Midazolam intravenous and oral clearances |
oral availability of Midazolam significantly lower in alcoholics than in the nonalcoholic, systemic and oral clearance of Midazolam was not altered, mRNA levels were not significantly different between the groups |
no correlation was observed between lymphocyte mRNA and in vivo activity |
[218] |
CYP3A | Demo graphi c factor |
Gender | Male, Female |
human plasma samples, human liver microsomes (HLM) |
Triazolam pharmacokinetics, Erythromycin demethylation N- |
no apparent gender differences in Triazolam pharmacokinetics observed, increase of activity in females comparing to males in Erythromycin demethylation N- |
[9,15] | |
CYP3A | Illness | Infectio n |
HBV chronic infection |
human liver samples, human liver microsomes (HLM) |
Western immunoblotting , activity measured in microsomes |
decrease of expression and activity |
[29] | |
CYP3A | Illness | Inflamm ation |
Cancer patients exhibiting clinical and laboratory features of an inflammat ory response |
human and animal studies |
in vivo and in vitro mechanistic studies |
decrease of expression |
[234] | |
CYP3A | Illness | Inflamm ation |
Inflammat ory bowel disease, Crohn′s disease |
clinical samples, duodenal biopsies |
RT-PCR | increase of mRNA expression |
[61] | |
CYP3A | Illness | Liver disease |
Alcoholic liver disease (ALD) |
liver biopsy samples | immunohistoch emistry, Western immunoblotting |
increase of protein level |
[225] | |
CYP3A | Illness | Liver disease |
Nonalcoh olic steatohepa titis (NASH) |
clinical samples, liver biopsy samples |
immunohistoch emistry |
decrease of protein level |
[224] | |
CYP3A | Physio logical conditi on |
Pregnan cy |
Pregnancy | clinical samples, urine samples |
Dextromethorp han/3- Hydroxymorphi nan urinary ratio |
increase of activity |
[53] | |
CYP3A4 | Demo graphi c factor |
Age | Adults aged less then 20 to over 60 years |
clinical samples, human liver samples, human liver microsomes (HLM) |
RT-PCR, Western immunoblotting |
increase of liver mRNA expression, positive correlation was found between the liver protein level and subject age |
[2,5,7,11] | |
CYP3A4 | Demo graphi c factor |
Age | Children, 1 to 17 years |
clinical samples, duodenal biopsies samples |
RT-PCR | decrease of mRNA expression, expression was high in the first year of life and decreased with age to reach lower values in older children (17 years) |
[62] | |
CYP3A4 | Physio logical conditi on |
Ambient osmolali ty |
Hypertoni c environme nt |
clinical samples, human-intestinal C2bbe1 cells, primary human colon epithelia, human colon carcinoma-derived cell line, and human hepatoma cell line HepG2, human primary hepatocytes in hypertonic media |
RT-PCR | increase of mRNA expression and protein level |
[43,44] | |
CYP3A4 | Physio logical conditi on |
Ambient osmolali ty |
Hypotonic environme nt |
clinical samples, human-intestinal C2bbe1 cells, primary human colon epithelia and human colon carcinoma-derived cell line, and human hepatoma cell line HepG2 |
RT-PCR | decrease of mRNA expression and protein level |
[44] | |
CYP3A4 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissue samples, blood samples |
RT-PCR, Western immunoblotting, erythromycin breath test, immunohistoch emistry |
Inconsistent results obtained - decrease of mRNA, protein expression and activity in tumor tissue, also no expression of protein, very low expression mRNA or not present in tumor and normal tissue samples, protein expressed in tumor and normal tissue samples, increased expression in tumors |
[34,35,40, 66,69, 233,263, 291,310] |
|
CYP3A4 | Illness | Cancer | Colorectal carcinoma |
clinical samples, adenomatous colonic and normal tissue endoscopy samples, primary colorectal cancer, lymph node metastasis, tumor microsomes, Human colorectal cancer cells (Caco-2) |
RT-PCR, Western immunoblotting |
expression of CYP mRNA similar among normal and adenomatous colonic tissues, decrease of protein level in tumor and normal tissue samples of patients with adenomas comparing to biopsies obtained from disease-free controls, high expression in normal colon |
correlation between expression and tumor stage reported |
[65,253, 263,268, 296,423] |
CYP3A4 | Illness | Cancer | Engelbret h-Holm- Swarm (EHS) sarcoma |
Engelbreth-Holm- Swarm sarcoma cells in transgenic mouse model incorporating human CYP3A4, liver tissue samples |
RT-PCR and Taqman technology, Midazolam sleep test, proteins were visualized by enhanced chemiluminesce nce and quantified using densitometric analysis |
decrease of mRNA expression, protein and activity in tumor- bearing transgenic mice |
down- regulation of hepatic human transgene proposed |
[30] |
CYP3A4 | Illness | Cancer | Esophagea l carcinoma |
clinical samples, esophageal squamous- cell carcinoma (SCC) carcinoma endoscopy tissue samples, esophagectomy specimens, Barrett′s esophagus, esophageal squamous mucosa |
RT-PCR, Western immunoblotting, immunohistoch emistry |
mRNA expression and protein level was significantly lower in malignant tissue than in normal tissue |
[31,307] | |
CYP3A4 | Illness | Cancer | Gastric carcinoma |
clinical samples, foveolar epithelium of the human stomach with intestinal metaplasia |
immunoblotting immunohistoch emistry, RT- PCR |
expressed in foveolar epithelium with intestinal metaplasia, not detected in foveolar epithelium without intestinal metaplasia |
[293] | |
CYP3A4 | Illness | Cancer | Large intestine tumor |
clinical samples, tumor and normal tissue samples |
RT-PCR, Western immunoblotting |
no difference in mRNA and protein expression between normal and tumor tissue |
[63] | |
CYP3A4 | Illness | Cancer | Lung carcinoma |
clinical tissue samples | RT-PCR, immunohistoch emistry |
expression of mRNA in tumor tissue, expression of protein in normal tissue |
[296] | |
CYP3A4 | Illness | Cancer | Lymphoid carcinoma |
clinical primary tumors tissue samples, 44 T- cell lymphomas |
immunoblotting immunohistoch emistry |
high expression in tumor tissue |
high tumor expression could be useful to predict poor response to the standard PTCL chemothera py |
[287] |
CYP3A4 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP3A4 | Illness | Cancer | Ovarian carcinoma and normal tissue |
clinical tissue samples, primary epithelial ovarian cancer |
immunoblotting, immunohistoch emistry |
expressed in normal tissue |
[252] | |
CYP3A4 | Illness | Cancer | Renal carcinoma |
clinical samples, renal cell carcinoma and normal tissue samples |
immunohistoch emistry, immunoblotting , RT-PCR |
expressed mRNA and protein in renal cell cancer and in normal tissue samples |
[261] | |
CYP3A4 | Demo graphi c factor |
Ethnicity | Japanese | clinical samples, liver samples |
RT-PCR | increase of mRNA expression comparing to Caucasians |
ethnic differences in the expression levels of adult liver CYP3A mRNAs between Japanese and Caucasians obtained |
[64] |
CYP3A4 | Demo graphi c factor |
Gender | Male, Female |
clinical samples, human liver and human endometrial samples, human liver microsomes (HLM), cryopreserved human hepatocytes |
RT-PCR, Western immunoblotting , Verapamil N- dealkylation, Testosterone hydroxylation C6beta- |
decrease of hepatic mRNA and protein levels in younger females comparing to younger males, decrease of mRNA expression in premenopausal women comparing to men, no difference in expression of mRNA in postmenopausal women comparing to men, down- regulation of mRNA expression in females by estrogen suggested, increase of mRNA expression and of activity in females group comparing to males when age influence of females has not been considered |
no clinically significant pharmacok inetic drug- drug interaction potential |
[2,3,11] |
CYP3A4 | Therap eutic conditi on |
Hypothe rmia |
Temperatu re decrease |
blood samples | Midazolam pharmacokineti cs |
decrease of activity |
[42] | |
CYP3A4 | Illness | Inflamm ation |
Inflammat ion after elective surgery |
breath test | carbon-14 [14C]Erythromycin demethylation |
decrease of activity with acute inflammation |
clinically significant drug-drug interaction potential |
[4] |
CYP3A4 | Illness | Inflamm ation |
Inflammat ory bowel disease, Crohn′s disease |
clinical samples, duodenal biopsies |
RT-PCR | increase of mRNA expression |
[61] | |
CYP3A4 | Illness | Obesity | Morbid obesity |
clinical studies | pharmacokineti c studies |
decrease of activity |
clinically significant pharmacok inetic drug- drug interaction potential |
[243] |
CYP3A4 | Physio logical conditi on |
Oxidativ e stress |
Reactive oxygen species, hydrogen peroxide |
human erythroleukemic cell line, K562 |
RT-PCR, Western immunoblotting |
increase of mRNA and protein expression |
oxidative stress may affect GST and/or CYP expression in human blood cells, which may alter the metabolism of drugs and xenobiotics |
[50] |
CYP3A5 | Demo graphi c factor |
Age | Adults | clinical samples, human liver samples |
RT-PCR |
Inconsistent results reported - increase of liver mRNA expression, also no difference observed with age |
[2,5] | |
CYP3A5 | Demo graphi c factor |
Age | Children, 1 to 17 years |
clinical samples, duodenal biopsies samples |
RT-PCR | decrease of mRNA expression with age without reaching statistical significance |
[62] | |
CYP3A5 | Physio logical conditi on |
Ambient osmolali ty |
Hypertoni c environme nt |
human-intestinal C2bbe1 cells, primary human colon epithelia and colon carcinoma- derived cell line, and human hepatoma cell line HepG2 |
RT-PCR | increase of mRNA expression and protein level |
[44] | |
CYP3A5 | Physio logical conditi on |
Ambient osmolali ty |
Hypotonic environme nt |
human-intestinal C2bbe1 cells, primary human colon epithelia and colon carcinoma- derived cell line, and human hepatoma cell line HepG2 |
RT-PCR | decrease of mRNA expression and protein level |
[44] | |
CYP3A5 | Illness | Cancer | Brain carcinoma |
clinical tissue samples, meningeomas, medulloblastoma grade IV |
RT-PCR | expressed in some of tumor tissue samples |
[296,299] | |
CYP3A5 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissue samples |
RT-PCR, Western immunoblotting |
Inconsistent results reported- expression of mRNA in tumor and normal tissue samples, also no expression reported |
[34,69] | |
CYP3A5 | Illness | Cancer | Colorectal carcinoma |
clinical samples, normal tissue and adenomatous colonic tissue endoscopy samples, primary colorectal cancer, Human colorectal cancer cells (Caco-2) |
RT-PCR, Western immunoblotting, immunohistoch emistry |
increase of mRNA expression in adenomatous colonic tissues, decrease of protein level in normal tissue of patients with adenomas comparing to biopsies obtained from disease-free controls |
correlation between expression and tumor stage reported |
[65,253, 423] |
CYP3A5 | Illness | Cancer | Esophagea l carcinoma |
clinical samples, esophageal squamous- cell carcinoma, SCC, carcinoma endoscopy tissue samples |
RT-PCR, Western immunoblotting |
increase of mRNA expression and protein in tumor comparing to normal tissue |
[31] | |
CYP3A5 | Illness | Cancer | Large intestine tumor |
clinical tumor tissue samples |
RT-PCR, Western immunoblotting |
no difference in mRNA and protein expression between normal and tumor tissue |
[63] | |
CYP3A5 | Illness | Cancer | Lung carcinoma |
clinical samples, non- small cell lung cancer tissue samples, A549 adenocarcinoma cell line |
RT-PCR, immunohistoch emistry, Northern blotting |
expression of mRNA and protein in tumor and normal tissue |
[263,265 ,266,296 ,309,337] |
|
CYP3A5 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non cancerous nasopharynx tissues |
[41] | |
CYP3A5 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian cancer |
immunoblotting, immunohistoch emistry |
high increase of expression in primary tumor tissue comparing to normal tissue |
[252] | |
CYP3A5 | Illness | Cancer | Prostate carcinoma |
clinical prostate tissue samples, microsomal fractions |
RT-PCR, Western immunoblotting, immunohistoch emistry, testosterone hydroxylation 6beta-, progesterone hydroxylation 6beta- |
Inconsistent results reported- expression of mRNA and protein in tumor and normal tissues, high expression and activity in normal tissue, also not expressed or decreased expression of mRNA and protein in tumor tissue |
[231,291 ,292,296 ,297,306] |
|
CYP3A5 | Illness | Cancer | Renal carcinoma |
clinical samples, renal cell carcinoma and normal tissue samples |
immunohistoch emistry, immunoblotting , RT-PCR |
expressed mRNA and protein in renal cell cancer and in normal tissue samples |
[261] | |
CYP3A5 | Enviro nment al conditi on |
Cigarett e smoke exposur e |
Cigarette smoke |
clinical samples, lung tissue samples, bronchoalveolar macrophages |
RT-PCR, immunoblotting |
expression of mRNA and protein in smokers and non- smokers |
proposed that CYP3A5 may be an important determinant in the activation of procarcinog ens present in cigarette smoke, and may contribute to the total burden of ultimate PAH carcinogens in human lung |
[336] |
CYP3A5 | Demo graphi c factor |
Ethnicity | Japanese | clinical samples, liver samples |
RT-PCR | increase of mRNA expression comparing to Caucasians |
ethnic differences in the expression levels of adult liver CYP3A mRNAs between Japanese and Caucasians obtained |
[64] |
CYP3A5 | Illness | Inflamm ation |
Inflammat ory bowel disease, Crohn′s disease |
clinical samples, duodenal biopsies |
RT-PCR | increase of mRNA expression |
[61] | |
CYP3A7 | Demo graphi c factor |
Age | Adults, | clinical samples, human liver samples |
RT-PCR | increase of liver mRNA expression with age |
[2] | |
CYP3A7 | Demo graphi c factor |
Age | Children, 1 to 17 years |
clinical samples, duodenal biopsies samples |
RT-PCR | no statistical relation with age in mRNA expression |
[62] | |
CYP3A7 | Physio logical conditi on |
Ambient osmolali ty |
Hypertoni c environme nt |
clinical samples, human-intestinal C2bbe1 cells, primary human colon epithelia and human colon carcinoma-derived cell line, and human hepatoma cell line HepG2 |
RT-PCR | increase of mRNA expression and protein |
[44] | |
CYP3A7 | Physio logical conditi on |
Ambient osmolali ty |
Hypotonic environme nt |
clinical samples, human-intestinal C2bbe1 cells, primary human colon epithelia and colon carcinoma- derived cell line, and human hepatoma cell line HepG2 |
RT-PCR | decrease of mRNA expression and protein level |
[44] | |
CYP3A7 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissue samples |
RT-PCR | expressed mRNA and protein in tumor and normal tissue samples |
[69] | |
CYP3A7 | Illness | Cancer | Large intestine tumor |
clinical samples, tumor tissue |
RT-PCR, Western immunoblotting |
no difference in mRNA and protein expression between normal and tumor tissue |
[63] | |
CYP3A7 | Illness | Cancer | Lung carcinoma |
clinical samples, lung cancer and normal tissue samples, A549 adenocarcinoma cell line |
RT-PCR, immunohistoch emistry, Northern blotting |
low or no mRNA expression of in tumor tissue and cells, expression in normal tissue, |
[266,337] | |
CYP3A7 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP3A7 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian tissue |
immunoblotting, immunohistoch emistry |
increase of expression in primary tumor tissue comparing to normal tissue high expression in metastatic ovarian tissue |
[252] | |
CYP3A7 | Illness | Cancer | Renal carcinoma |
clinical samples, renal cell carcinoma and normal tissue samples |
immunohistoch emistry, immunoblotting , RT-PCR |
expressed mRNA and protein in renal cell cancer and in normal tissue samples |
[261] | |
CYP3A7 | Demo graphi c factor |
Ethnicit y |
Japanese | clinical samples, liver samples |
RT-PCR | increase of mRNA expression comparing to Caucasians |
ethnic differences in the expression levels of adult liver CYP3A mRNAs between Japanese and Caucasians obtained |
[64] |
CYP3A43 | Demo graphi c factor |
Age | Adults | clinical samples, human liver samples |
RT-PCR | increase of liver mRNA expression with age |
[2,5] | |
CYP3A43 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer |
immunoblotting, immunohistoch emistry |
low expression, increase of expression comparing to normal tissue |
correlation between expression and tumor stage reported |
[253] |
CYP3A43 | Demo graphi c factor |
Gender | Male, Female |
clinical samples, human liver and human endometrial samples |
RT-PCR | decrease of mRNA expression in premenopausal women, down- regulation of mRNA expression in females by estrogen suggested, no difference in hepatic mRNA levels |
no clinically significant pharmacok inetic drug- drug interaction potential |
[2] |
CYP3F1 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non cancerous nasopharynx tissues |
[41] | |
CYP4A11 | Demo graphi c factor |
Age | Adults aged less then 20 to over 60 years |
clinical samples, liver and kidney cortex autopsy samples, human liver microsomes (HLM) |
Lauric acid hydroxylation C12- (omega -) |
increase of activity with age |
[11] | |
CYP4A11 | Enviro nment al conditi on |
Cadmiu m e xposur e |
Cadmium | clinical samples, kidney cortex and liver autopsy samples, human kidney microsomes, human liver microsomes (HLM) |
Western immunoblotting |
liver protein levels were positively correlated with tissue Cd content while in contrast kidney protein abundance was inversely correlated with kidney Cd burden |
[1,24] | |
CYP4A11 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissue samples |
RT-PCR | expressed mRNA and protein in tumor and normal tissue samples |
[70] | |
CYP4A11 | Illness | Liver disease |
Chronic hepatitis |
clinical samples, liver autopsy samples, human liver microsomes (HLM) |
Western immunoblotting |
decrease of protein level |
[24] | |
CYP4A11 | Illness | Liver disease |
Fatty liver | clinical samples, liver autopsy samples, human liver microsomes (HLM) |
Western immunoblotting |
decrease of protein level |
[24] | |
CYP4B1 | Illness | Cancer | Bladder carcinoma |
clinical samples, tumor and normal tissue samples, human bladder microsomes |
RT-PCR, Western immunoblotting, immunochemist ry, 2- aminofluorene activation |
increase of expression of mRNA, protein and activity in patients with tumor compared to no tumor patients |
suggested that high expression increases the risk of bladder tumor |
[304] |
CYP4B1 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissue samples |
RT-PCR | mRNA present in tumor and normal tissues samples, no qualitative differences expression at mRNA level between tumor and surrounding normal breast tissue samples |
[69] | |
CYP4B1 | Illness | Cancer | Lung carcinoma |
clinical samples, non- small cell lung cancer tissue samples |
RT-PCR, immunohistoch emistry |
decrease of mRNA expression in tumor tissue, expressed in normal tissue |
[263,264 ,296] |
|
CYP4B1 | Illness | Cancer | Nasophary ngeal carcinoma (NPC) |
NPC and non- cancerous nasopharynx tissue samples |
RT-PCR | mRNA present in NPC and non- cancerous nasopharynx tissues |
[41] | |
CYP4B1 | Illness | Cancer | Prostate carcinoma |
clinical prostate and normal tissues samples |
RT-PCR | expression of mRNA in tumor and normal tissues |
[291,292 ,306] |
|
CYP4F2 | Enviro nment al conditi on |
Cadmiu m exposur e |
Cadmium (Cd) |
clinical samples, kidney cortex autopsy samples, human kidney microsomes |
Western immunoblotting |
increase of protein expression with increased Cd accumulation |
[28] | |
CYP4V2 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer, lymph node metastasis |
immunoblotting, immunohistoch emistry |
low or no expression in tumor tissue |
correlation between expression in primary tumors and correspondi ng lymph node metastases |
[253] |
CYP4X1 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer |
immunoblotting, immunohistoch emistry |
low expression but increase of expression comparing to normal tissue |
correlation between expression and tumor stage reported |
[253] |
CYP4Z1 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples |
RT-PCR, immunoblotting |
low expression in normal colon, increase of mRNA and protein expression in tumor tissue samples, expressed in normal breast tissues |
[247] | |
CYP4Z1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian cancer |
immunoblotting, immunohistoch emistry |
increase of expression in primary tumor tissue comparing to normal tissue |
negative or low or moderate expression compared to high expression associated with poor survival |
[252] |
CYP5A1
(Thrombo xane A2, TXA(2), synthase) |
Illness | Cancer | Colorectal carcinoma |
clinical samples, colorectal cancer tissue and its accompanying normal mucosa, human colonic cancer cell lines |
RT-PCR, Western immunoblotting |
increase of mRNA and protein expression |
[32] | |
CYP5A1
(Thrombo xane A2, TXA(2), synthase) |
Illness | Cancer | Papillary thyroid carcinoma |
clinical samples, carcinoma and adjacent normal tissue, human papillary thyroid cell line TPC-1 |
RT-PCR | increase of mRNA expression |
[71,74] | |
CYP5A1
(Thrombo xane A2, TXA(2), synthase) |
Illness | Cancer | Pituitary adenomas and carcinoma s |
clinical samples, tumor and normal pituitaries |
immunohistoch emistry, RT- PCR |
increase of expression |
[73] | |
CYP5A1
(Thrombo xane A2, TXA(2), synthase) |
Illness | Cancer | Prostate carcinoma |
clinical samples, prostate cancer cells and normal prostate epithelial cells |
RT-PCR, Western immunoblotting |
increase of mRNA and protein expression, low expression in normal cells |
[72] | |
CYP7B1 | Illness | Cancer | Colorectal carcinoma |
clinical cancer tissue samples |
RT-PCR, Western immunoblotting |
increase of mRNA and protein expression |
[33] | |
CYP7B1 | Illness | Cancer | Prostate carcinoma |
clinical prostate tissue samples and prostate cancer cell lines |
RT-PCR, Western immunoblotting |
increase of mRNA and protein expression in prostatic intraepithelial neoplasia (PIN) and adenocarcinomas |
[33] | |
CYP11A1 | Illness | Cancer | Breast carcinoma |
clinical samples, tumor and normal tissues samples |
RT-PCR | mRNA present in tumor and normal tissues samples, no qualitative differences in CYP expression at mRNA level between tumor and surrounding normal breast tissues samples |
[69] | |
CYP19A1
(Aromatas e) |
Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples |
RT-PCR | mRNA and protein present in tumor and control tissues, in the course of the disease a switch of promoter occurs and results in higher expression levels, also high incidence of no expression reported in postmenopausal women |
patients with expression of tumor aromatase (CYP19) had a better prognosis than patients with no expression of this transcript |
[70,236, 385] |
CYP19
(Aromatas e) |
Illness | Cancer | Gastric carcinoma |
clinical tumor and adjacent no tumor tissue samples, intestinal-type and diffuse-type adenocarcinomas, gastric cancer cell lines |
immunohistoch emistry, RT- PCR, Western immunoblotting |
expression of mRNA in gastric cancer cell lines, expression of mRNA and protein in cancer and in no tumor mucosa tissue |
[383] | |
CYP19
(Aromatas e) |
Illness | Cancer | Lung carcinoma |
clinical tumor tissue samples, non-small cell lung cancer tissue |
RT-PCR | expression of mRNA in tumor tissue |
[36] | |
CYP19
(Aromatas e) |
Illness | Cancer | Ovarian carcinoma |
clinical tumor and no tumor tissue samples, ovarian epithelial cancer cell lines, ovarian epithelial cancers |
immunohistoch emistry, RT- PCR, Western immunoblotting |
decreased expression of mRNA, protein and activity in some ovarian epithelial cancer cells and tissues comparing to normal ovarian epithelial tissues |
no significant differences in aromatase expression were observed according to the tumor histotype (endometrio id, mucinous, serous papillary and undifferenti ated histotype), grade or stage |
[384] |
CYP24A1 | Illness | Cancer | Lung carcinoma |
non-small cell lung cancer tissue samples |
RT-PCR | mRNA expression in tumor tissue |
[36] | |
CYP26A1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian cancer |
immunoblotting, immunohistoch emistry |
high increase of expression in primary tumor tissue comparing to normal tissue |
[252] | |
CYP39 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer, lymph node metastasis |
immunoblotting, immunohistoch emistry |
low expression in tumor tissue |
correlation between expression in primary tumors and correspondi ng lymph node metastases |
[253] |
CYP51A1 | Illness | Cancer | Colorectal carcinoma |
clinical tissue samples, primary colorectal cancer |
immunoblotting, immunohistoch emistry |
increase of expression comparing to normal tissue |
high expression associated with poor prognosis |
[253] |
CYP51A1 | Illness | Cancer | Ovarian carcinoma |
clinical tissue samples, primary epithelial ovarian cancer and metastatic ovarian cancer |
immunoblotting, immunohistoch emistry |
increase of expression in primary tumor tissue comparing to normal tissue |
[252] | |
total CYP | Illness | Liver disease |
Postoperat ive septic liver failure |
clinical samples, survivors and no survivors |
Aminopyrine breath test |
decrease of activity |
suggested as clinically useful tool for predicting the outcome in the early stages of sepsis |
[214] |
Table 2. Effects of selected effectors on expression and activity of transporters in humans.
Transpo rter |
Category | Subcate gory |
Effectors | Model | Method | Effect | Remarks | Reference s |
---|---|---|---|---|---|---|---|---|
ABCA1,
ABC1 |
Illness | Endothel ial cell dysfuncti on |
Uremic plasma |
clinical samples, human coronary arterial endothelial cells |
RT-PCR, microarra y |
decrease of mRNA expression |
[208] | |
ABCA1,
ABC1 |
Physiologic al condition |
Oxidativ e stress |
Reactive oxygen species |
CuSO(4) generated, J774 macrophages, normal human skin fibroblast and Tangier fibroblasts |
Western immunobl otting, cholestero l and phospholi pids efflux |
increase of activity |
[204] | |
ABCB11,
BSEP |
Illness | Liver disease |
Cholecyst cholesterol lithiasis |
clinical samples, liver tissue samples |
RT-PCR, Western immunobl otting |
increase of mRNA and protein expression |
[90] | |
ABCG1,
ABC8 |
Illness | Endothel ial cell dysfunction |
Uremic plasma |
clinical samples, human coronary arterial endothelial cells |
RT-PCR, microarra y |
decrease of mRNA expression |
[208] | |
ABCG2,
MXR, BCRP1, ABCP |
Illness | Cancer | Bladder carcinoma |
clinical tumor tissue samples |
immunohi stochemist ry |
high protein expression |
no prognostic impact |
[401] |
ABCG2,
MXR, BCRP1, ABCP |
Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples, primary breast cancers, MCF7 and BT20 breast cancer cell lines |
RT-PCR, immunohi stochemist ry, Northern blotting |
low expression of mRNA in tumor samples, protein detected in normal duct cells but not in tumor cells, mRNA and protein expressed at higher level in MCF7 and BT20 breast cancer cell lines then in tumor samples |
Inconsistent results reported - suggested that may play a role in anthracycline resistance, reported not to relate to the relapse or prognosis in patients treated with doxorubicin- based chemotherapy , also no indication that elevated expression in breast carcinomas confers resistance to anthracyclines, high tumor malignancy grade was associated with a decreased mRNA expression, survival and disease-free survival were not significantly associated with BCRP mRNA expression |
[344,398,422] |
ABCG2,
MXR, BCRP1, ABCP |
Illness | Cancer | Leukemia | clinical tumor tissue samples, acute lymphocytic (lymphoblastic) leukemia (ALL), adult acute myeloid leukemia (AML), bone marrow samples |
RT-PCR, immunobl otting |
increase of mRNA expression, functional assay, expression of protein in PC13 2- 2 and HL60/MRP cell lines |
Inconsistent results reported - suggested to be involved in chemoresistance, coexpression of MDR1/BCRP in AML patients was associated with a lower complete response (CR) rate and with worse event-free and overall survival, suggested as a prognostic factor in AML patients, might contribute to drug resistance in B-lineage ALL, also no association between BCRP overexpression and unfavorable outcome in ALL patients reported |
[345,357,377,411,412] |
ABCG2,
MXR, BCRP1, ABCP |
Illness | Cancer | Liver carcinoma |
clinical tumor tissue samples, hepatocellula r carcinoma (HCC) , HepG2 cell line |
RT-PCR, immunohistochemistry |
expression of mRNA as in normal tissue |
could be up- regulated by anti- cancer agents in vitro |
[396,397] |
ABCG2,
MXR, BCRP1, ABCP |
Illness | Cancer | Lymphoid carcinoma |
clinical tumor tissue samples, T/NK-cell lymphomas |
immunohi stochemistry |
expression of protein |
[399] | |
ABCG2,
MXR, BCRP1, ABCP |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
Saos-2, JAR, OCI-AML3 cells |
RT-PCR, Hoechst 33342 efflux |
increase of mRNA, protein expression and activity |
suggested that increase of expression could lead to increased chemotherapeutic resistance to compounds that are BCRP substrates |
[188] |
ABCG2,
MXR, BCRP1, ABCP |
Illness | Liver disease |
Acetaminop hen overdoses |
clinical samples, injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplificati on assay, immunohi stochemist ry |
increase of protein level |
[205] | |
ABCG2,
MXR, BCRP1, ABCP |
Illness | Liver disease |
Primary biliary cirrhosis |
clinical samples, injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplification assay, immunohisto chemist ry |
increase of mRNA expression and protein level |
[205] | |
AE2,
SLC4A2 |
Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples, hepatocellula r carcinoma (HCC) and paired adjacent normal liver tissue samples |
RT-PCR, Western immunobl otting |
increase of mRNA and protein expression |
[86] | |
ASCT1,
SATT, SLC1A4 |
Illness | Cancer | Esophageal carcinoma |
clinical tumor tissue samples, esophageal carcinomas tissue samples, squamous cell carcinoma, adenocarcinoma |
immunohi stochemist ry |
increase of mRNA expression in adenocarci nomas comparing to squamous cell carcinomas |
[104] | |
ASCT2,
AAAT, SLC1A5 |
Illness | Infection | Legionella pneumophil a infection |
clinical samples, Mono Mac 6 cells, human isolate from a patient with severe Legionella pneumonia |
RT-PCR, Western immunobl otting |
increase of mRNA expression |
[194] | |
ASCT2,
AAAT, SLC1A5 |
Illness | Ischemia | Restriction in blood supply |
ischemic injured Caco- 2 cell lines |
RT-PCR, Western immunobl otting, Glutamine transport |
decrease of mRNA expression, protein level and activity |
[192] | |
ATA1,
SNAT1, NAT2, SAT1, SLC38A 1 |
Nutritional condition |
Amino acid depletion |
Neutral amino acids depletion |
BeWo choriocarcino ma cell line |
RT-PCR, Northern blotting, Western immunobl otting, immunocy tochemistr y, radiolabel ed amino acids uptake, N-(methylam ino)isobut yric acid (MeAIB) transcellul ar transport |
no effect in BeWo cells, or decrease of mRNA expression after long- term incubation |
[195,199] | |
ATA1,
SNAT1, NAT2, SAT1, SLC38A 1 |
Illness | Cancer | Liver carcinoma |
HepG2, HLF, HuH7 and JHH4 cell lines, surgical pre-malignant cirrhotic livers, hepatocellula r carcinoma (HCC) and non-cancerous liver tissue samples |
RT-PCR, immunohi stochemist ry |
increase of mRNA expression and protein level compared to non- cancerous liver cells |
[96] | |
ATA1,
SNAT1, NAT2, SAT1, SLC38A 1 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
cultured term human trophoblasts, gas mixture |
Northern blotting, Alanine uptake |
decrease of expression and activity |
[185] | |
ATA2,
SNAT2, SAT2, SLC38A 2 |
Nutritional condition |
Amino acid depletion |
Neutral amino acids depletion |
BeWo choriocarcino ma cell line, HepG2 human hepatoma cells, HeLa and C6 cells |
RT-PCR, Northern blotting, Western immunobl otting, immunocy tochemistry radiolabel ed amino acids uptake, MeAIB transcellular transport |
increase of mRNA, protein expression and activity after long-term incubation |
[196,197,198,199] | |
ATA2,
SNAT2, SAT2, SLC38A 2 |
Illness | Cancer | Liver carcinoma |
HepG2, HLF, HuH7 and JHH4 cell lines, surgical pre-malignant cirrhotic livers, hepatocellula r carcinoma and non- cancerous liver tissue samples |
RT-PCR, immunohi stochemist ry |
increase of mRNA expression and protein level compared to non- cancerous liver cells |
[96] | |
ATA2,
SNAT2, SAT2, SLC38A 2 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
cultured term human trophoblasts, gas mixture |
Northern blotting, Alanine uptake |
decrease of expression and activity |
[185] | |
ATB0,+,
SLC6A1 4 |
Illness | Cancer | Cervical carcinoma |
clinical tumor and normal tissue samples, normal ectocervical mucosa and cervical squamous cell carcinoma |
RT-PCR, immunohi stochemist ry, immunofl uorescenc e |
increase of mRNA expression and protein level |
[85] | |
ATB0,+, SLC6A1 4 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor tissue samples, carcinoma and control tissue from colectomy samples, liver tissue, lymph node metastases |
RT-PCR, Western immunobl otting |
increase of mRNA and protein expression |
[84] | |
BGT1,
SLC6A1 2 |
Physiologic al condition |
Cellular osmolalit y |
Hypertonic environmen t |
HaCaT keratinocytes, primary normal human keratinocytes, hyperosmotic exposure |
RT-PCR, osmolyte uptake |
increase of mRNA expression and activity |
[178,212] | |
BGT1,
SLC6A1 2 |
Physiologic al condition |
Cellular osmolalit y |
Hypotonic environmen t |
primary normal human keratinocytes hyperosmotic exposure |
osmolyte efflux |
increase of activity |
[212] | |
BGT1,
SLC6A1 2 |
Experiment al condition |
Cellular osmolalit y |
Ultraviolet A and B radiation |
primary normal human keratinocytes, hyperosmotic exposure |
RT-PCR, osmolyte uptake |
increase of mRNA expression and activity |
[212] | |
CNT1,
SLC28A 1 |
Illness | Infection | HIV-1 viral infection |
clinical samples, adipose tissue, adipocytes |
RT-PCR | increase of mRNA expression |
[94] | |
CNT2,
SLC28A 2 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
HepG2 human hepatocellula r carcinoma, Hep3B human hepatocellula r carcinoma, Panc-1human pancreatic carcinoma, and A673 human rhabdomyosa rcoma cells |
RT-PCR | decrease of expression |
[180] | |
CNT3,
SLC28A 3 |
Illness | Infection | HIV-1 viral infection |
clinical samples, adipose tissue, adipocytes |
RT-PCR | increase of mRNA expression |
[94] | |
ENT1,
SLC29A 1 |
Demographi c factor |
Hypoxia | Decreased oxygen pressure |
human umbilical vein endothelium (HUVEC), HepG2 human hepatocellula r carcinoma, Hep3B human hepatocellula r carcinoma, Panc-1human pancreatic carcinoma, and A673 human Rhabdomyos arcoma cells, gas mixture exposure |
RT-PCR, Adenosine transport, Western immunobl otting |
decrease of mRNA expression, protein level and activity |
[179,180] | |
ENT1,
SLC29A 1 |
Physiologic al condition |
Oxidativ e stress |
Reactive oxygen species |
human neuroblastom a SH-SY5Y cells transfected with either familial amyotrophic lateral sclerosis- typical G93A mutant or wild-type copper/zinc superoxide dismutase |
Glutamate transport |
impaired function |
[200] | |
ENT2,
SLC29A 2 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
clinical samples, HepG2 human hepatocellula r carcinoma, Hep3B human hepatocellula r carcinoma, Panc-1human pancreatic carcinoma, and A673 human Rhabdomyos arcoma cells |
RT-PCR | decrease of expression |
[180] | |
ENT2,
SLC29A 2 |
Illness | Infection | HIV-1 viral infection |
clinical samples, adipose tissue, adipocytes |
RT-PCR | increase of mRNA expression |
[94] | |
ENT3,
SLC29A 3 |
Physiologic al condition |
Oxidativ e stress |
Reactive oxygen species |
human neuroblastom a SH-SY5Y cells transfected with either familial amyotrophic lateral sclerosis- typical G93A mutant or wild-type copper/zinc superoxide dismutase |
Glutamate transport |
impaired function |
[200] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Bladder carcinoma |
clinical tumor tissue samples, transitional cell carcinoma |
immunohi stochemist ry |
increase of protein expression in invasive or extensive disease, not expressed in normal bladder or benign papilloma samples |
suggested as a marker of aggressive biologic potential, strongly associated with the neoplastic progression |
[108,112,133] |
GLUT1,
SLC2A1 |
Illness | Cancer | Brain carcinoma |
clinical tumor tissue samples, embryonal neoplasm, cerebellar medulloblast oma, medulloblast oma cell line |
Western immunobl otting |
expressed in cell membranes of neoplastic cells, not expressed in non- embryonal neoplasm |
suggested as useful marker to define the embryonal nature of primitive undifferentiated small cell neoplasm of CNS |
[125] |
GLUT1,
SLC2A1 |
Illness | Cancer | Brain carcinoma |
clinical malignant and normal tissue samples, malignant glial cells, choroid plexus papilloma, meningioma, glioma, ependymoma , and astrocytoma biopsies |
immunohi stochemist ry, autoradiog raphy |
increase of mRNA and protein expression, weak to moderate expression in tumor tissue, weak expression in normal tissue, decrease of protein expression in malignant choroid plexus reported |
mRNA expression suggested as a marker of aggressive biologic potential and potential targets for future therapy |
[113,116,151,155,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples, tumor and adjacent normal breast tissues samples, benign and malignant cell line, breast cancer cell lines MCF-7, MDA-468, and ZR-75-1 |
immunohi stochemist ry, immunobl otting, Deoxyglu cose uptake, in situ RT- PCR |
increase of mRNA and protein expression in breast cancer cells and cancer tissue compared with the healthy breast tissue, very weak expression in ductal epithelial cells, or not expressed in normal breast tissue |
suggested as a marker of aggressive biologic potential associated with poor survival of patients; increase of mRNA, protein expression and activity by progesterone and estrogen treatment |
[88,107,110,114,117, 118,119,157,173,175,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Cervical carcinoma |
clinical tumor and normaltissue samples, biopsy samples, cervical squamous carcinoma and normal cervical tissue samples |
immunohi stochemist ry |
increase of expression in cancer specimens, no or low expression in normal tissues |
absence of Glut-1 significantly increased the likelihood of metastasis-free survival (P = 0.022) but did not significantly effect disease- free or recurrence-free survival, suggested as a prognostic marker for metastases-free survival and related to grade of tumor |
[120,153,154] |
GLUT1,
SLC2A1 |
Illness | Cancer | Cholangioc arcinoma |
clinical tumor tissue samples |
immunohi stochemist ry |
increase of expression, not present in normal tissue or benign bile ductule proliferatio ns |
suggested as reliable marker for detection of bile duct carcinoma |
[160] |
GLUT1,
SLC2A1 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples, primary c olon cancer tissue, colorectal neoplastic endoscopic or surgical tissue samples, normal colon, benign colon adenomas and colorectal carcinoma tissue samples, normal and colon cancer cells transplanted in nude mice, invasive tubular carcinoma |
immunohi stochemist ry, RT- PCR, Western immunobl otting, (18)F-FDG uptake, Northern blotting |
increase of mRNA and protein expression and activity in cancer tissue and cells, central part of the tumor thought to be relatively hypoxic had stronger expression, not expressed in normal tissue |
suggested as a marker for poor prognosis and poor survival of patients, suggested as noninvasive biomarker for advanced tumor indicative of a large hypoxic tumor with deep invasion, associated with poor survival of patients |
[88,121,122,123,128, 162,164,173,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Cutaneous carcinoma |
clinical tumor tissue samples, squamous cell carcinoma samples |
immunohi stochemist ry |
increase of expression |
[124] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Esophageal carcinoma |
clinical tumor tissue samples, esophageal carcinomas tissue samples, squamous cell carcinoma, adenocarcino ma |
immunohi stochemist ry |
increase of mRNA expression in adenocarci nomas and squamous cell carcinomas |
[104] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Gastric carcinoma |
clinical tumor and normal tissue samples, adenocarcino ma |
immunohi stochemist ry, RT- PCR |
increase of mRNA and protein expression with tumor progression , low expression in stomach adenocarci noma, not expressed in normal tissue |
suggested as tumor marker in the diagnosis and prognosis of gastric malignancies, not expressed in normal tissue |
[126,127,151,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Head and neck carcinoma |
clinical tumor and normal tissue samples, head and neck squamous cell carcinoma, tissue of head and neck tumors, adjacent mucosa, and normal mucosa samples, biopsy (FNAB) material |
immunohi stochemist ry |
increase of protein expression, increase of expression in hypoxic regions, expression of mRNA and protein |
suggested as reliable marker in the diagnosis of premalignant lesions of the oropharyngeal mucosa and that combination of an antitumor agent with inhibitors of GLUT1 would be beneficial to the cancer therapy, also high GLUT expression observed in some tumors was not associated with amplification or rearrangement of the corresponding genes, gene expression level and protein expression were correlated with lymph node metastases, poor survival and clinical stage |
[129,130,131,132] |
GLUT1,
SLC2A1 |
Illness | Cancer | Kidney carcinoma |
clinical tumor and normal tissue samples, kidney surgical samples, renal cell carcinoma (RCC), papillary RCC, chromophobe RCC and oncocytoma tumors |
RT-PCR, immunohi stochemist ry |
Increase or decrease of mRNA expression in tumor cells, expressed in normal tissue |
[161,177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Laryngeal carcinoma |
clinical tumor tissue samples, biopsy samples of squamous cell carcinoma (SCC) of the larynx |
immunohi stochemist ry, RT- PCR |
mRNA expressed |
not associated with poor survival of patients |
[174] |
GLUT1,
SLC2A1 |
Illness | Cancer | Leiomyosar coma |
clinical tumor tissue samples, extrauterine and uterine leiomyosarco ma tissue samples |
immunohi stochemistry |
increase of expression, not present in leiomyoma tissues |
positivity closely correlated with aggressive biologic behavior |
[134] |
GLUT1,
SLC2A1 |
Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples, liver vascular tumor pathology samples from biopsy, excision, or autopsy tissue samples |
immunohi stochemist ry |
increase of expression, not expressed or low level in normal tissue |
suggested as specific for proliferating hemangioma, and its expression predicts the typical course of proliferation followed by involution |
[159,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples, normal fibroplast and hepatocellula r carcinoma (HCC), HepG2 cells injected into the intraportal vein of SCID mice, hepatocellula r carcinoma |
immunohi stochemist ry, Western immunobl otting, (18)F-FDG uptake |
increase of expression and activity, not expressed in normal tissue |
[162,165,177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissue samples, non- small cell lung cancer (NSCLC) |
immunohi stochemist ry, RT- PCR |
increase of mRNA, protein expression and activity, not expressed in normal tissue |
suggested as a significant poor prognosis indicator in cases of NSCLC, associated with a lower degree of tumor differentiation, not expressed in normal tissue |
[109,115,136,137,138,139,151, 177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Lung carcinoma |
clinical tumor tissue samples, bronchioloalv eolar carcinomas and non- bronchioloalv eolar carcinomas; |
immunohi stochemist ry |
decrease of expression and activity, significantl y lower in bronchioloa lveolar carcinomas than in non-bronchioloa lveolar carcinomas |
associated with poor survival of patients |
[135,173] |
GLUT1,
SLC2A1 |
Illness | Cancer | Lung carcinoma-Brain metastases |
clinical tumor tissue samples, hematogenou s metastases brain tissue samples |
immunohi stochemist ry |
decrease of expression, significantl y lower comparing to endothelial cells of microvessel s around the metastases |
[140,151] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Lymphoid carcinoma |
clinical tumor tissue samples, Hodgkin’s lymphoma biopsies samples |
immunohi stochemist ry |
not expressed in tumor tissue |
[177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Lymphoid carcinoma |
clinical tumor tissue samples, Non-Hodgkin’s lymphoma biopsies |
immunohi stochemist ry |
low expression in tumor tissue |
[177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Ovarian carcinoma |
clinical malignant and normal tissue samples, borderline, benign epithelial tumor |
immunohi stochemist ry |
increase of protein expression, progressive ly more staining in invasive tumors as compared to borderline tumors, not expressed in benign ovarian epithelial tumors and normal tissue |
suggested as clinically useful prognostic information in patients with ovarian carcinoma, associated with a lower degree of tumor differentiation and with poor survival of patients |
[141,147,148,173,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Pancreatic carcinoma |
clinical tumor and normal tissue samples, transfected pancreatic cancer cell lines MIAPaCa-2, PANC-1, BXPC-3, and CAPAN-2, adenocarcino ma and neuroendocri ne tumor biopsies |
Northern blotting, RT-PCR, immunohi stochemist ry, Western immunobl otting |
increase of mRNA and protein expression and activity, also low expression in adenocarci noma, not expressed in normal tissue |
suggested as a fruitful target for therapeutic strategies aimed at suppression of tumor glycolysis, promotes pancreatic cellular invasiveness, and its expression is associated with pancreatic cancer invasiveness |
[142,151,152,156,158,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Penile carcinoma |
clinical malignant tissue samples |
immunohi stochemist ry |
increase of protein expression |
1 [43] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Prostate carcinoma |
clinical prostate carcinoma tissue samples, prostate cancer cells and cultured prostate cancer cell line LNCaP, C4, C4-2, and C4-2B using primers to amplify GLUT1, benign prostatic hyperplasia |
RT-PCR, immunohi stochemist ry |
protein weakly or not expressed in malignant tissue, mRNA and protein expressed in benign prostatic hyperplasia and in carcinoma cell lines, expressed in normal tissue |
[176,177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Renal carcinoma |
clinical tumor tissue samples, tissue samples of renal transitional cell carcinoma and renal clear cell carcinoma |
immunohi stochemist ry |
increase of expression, not present in normal tissue |
strongly associated with the neoplastic progression |
[133] |
GLUT1,
SLC2A1 |
Illness | Cancer | Skeletal muscle carcinoma |
clinical tumor and normal tissue samples, Rhabdomyosar coma biopsies |
immunohi stochemist ry |
not expressed in tumor or normal tissue |
[177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Skin carcinoma |
clinical tumor and normal tissue samples, melanoma biopsies |
immunohi stochemist ry |
not expressed in tumor, low expression in normal tissue |
[177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Testicular carcinoma |
clinical tumor and normal tissue samples, seminoma and embryonal cancer biopsies |
immunohi stochemist ry |
expressed as in normal tissue |
[177] | |
GLUT1,
SLC2A1 |
Illness | Cancer | Thyroid carcinoma |
clinical tumor and normal tissue samples, papillary carcinoma biopsies |
immunohi stochemist ry, RT- PCR |
increase of mRNA and protein expression, not expressed in papillary carcinoma biopsies, not expressed in normal breast tissue |
suggested as a prognostic marker for thyroid cancer |
[106,144,145,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Uterus carcinoma |
clinical tumor and normal tissue samples, endometrial adenocarcino ma, hyperplasia, leimyeoma and normal tissue samples |
immunohi stochemist ry |
Inconsiste nt results reported -increase of protein expression or low expression, not expressed in all atypical complex hyperplasia, benign endometrial epithelium as well as cystic, complex hyperplasia and normal tissue |
GLUT1 immunoreactivity in endometrial hyperplasia appears to be a useful indicator of high risk for development of endometrial carcinoma |
[146,177] |
GLUT1,
SLC2A1 |
Illness | Cancer | Vascular carcinoma |
clinical tumor tissue samples, surgical tissue samples of postnatal proliferating infantile hemangioma |
immunohi stochemist ry |
increase of protein expression, nonprogres sive lesions showed complete lack of immunorea ctivity |
[150] | |
GLUT1,
SLC2A1 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
clinical samples, CoCl(2) induced hypoxia, biopsies samples, cervical squamous carcinoma cells, cultured human cervical cancer cell line HeLa, primary syncytotroph oblast cell, BeWo choriocarcino ma cells and human placental villous tissue explants |
immunohi stochemist ry, RT- PCR, immunobl otting, Northern blotting |
increase of mRNA, protein expression and activity |
weak correlation between Glut-1 expression and tumor pO(2) measurements |
[120,168,169,170,171,172,173] |
GLUT1,
SLC2A1 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
clinical samples, chronic placental hypoxia, placenta basal membrane fractions and syncytial microvillous from normal term pregnancy |
immunobl otting |
decrease of expression |
[167] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Brain carcinoma |
clinical tumor and normal tissue samples, choroid plexus papilloma, ependymoma |
immunohi stochemist ry |
weak to moderate expression, no expression in normal tissue |
[177] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples, benign and malignant cell line, breast cancer cell lines MCF-7 and MDA-468 |
immunocy tochemistry immunobl otting, Deoxyglu cose uptake, Western blotting, immunohi stochemist ry, in situ RT-PCR |
Inconsiste nt results reported -expressed in breast cancer cell lines, increase of expression in ductal invasive carcinoma; no increase of mRNA, protein expression and activity by progesteron e and estrogen treatment, expressed or not expressed in normal breast tissue |
protein levels decreased with invasive potential |
[110,107, 157,177] |
GLUT2,
SLC2A2 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples, normal colon, benign colon adenomas and colorectal carcinoma tissue samples, normal and colon cancer cells transplanted in nude mice, invasive tubular carcinoma |
RT-PCR, Northern blotting |
Inconsiste nt results reported -mRNA expression similar in cancer and normal tissue, also no expression in colon cancer tumors or normal tissue |
[128,164,177] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Gastric carcinoma |
clinical tumor tissue samples |
immunohi stochemist ry, RT- PCR |
increase of mRNA expression, not expressed in normal tissue |
[127,151,177] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Kidney carcinoma |
clinical tumor tissue samples, kidney surgical samples, renal cell carcinoma (RCC), chromophobe RCC and oncocytoma tumors, clear cell RCC and papillary RCC |
RT-PCR | decrease of mRNA expression in tumor cells, or mRNA expression in tumor cells as expressed in normal tissue |
[161] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples, hepatocellula r carcinoma |
immunohi stochemist ry, Western immunobl otting, (18)F-FDG uptake |
increase of expression and activity, expressed in normal tissue |
suggested that combined evaluation of 18F-FDG uptake and expression of Glut-2 might have an important role for management of patients |
[165,177 |
GLUT2,
SLC2A2 |
Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissue samples, mesothielom a |
immunohi stochemist ry |
low expression, not expressed in normal tissue |
[177] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Ovarian carcinoma |
clinical malignant and normal tissue samples |
immunohi stochemist ry |
weak expression or no expression, not expressed in normal tissue |
[177] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Pancreatic carcinoma |
clinical malignant and normal tissue samples, adenocarcino ma, insulinomas, glucagonoma s and their lymph node metastases, and gastrinoma |
Northern blotting, Western immunobl otting, RT-PCR, immunohi stochemist ry |
decrease of mRNA expression comparing to normal islets, expressed in normal human pancreatic islets |
[151,152,177] | |
GLUT2,
SLC2A2 |
Illness | Cancer | Uterus carcinoma |
clinical tumor and normal tissue samples, leimyeoma |
immunohi stochemist ry |
expressed in tumor tissue, not expressed in normal tissue |
[177] | |
GLUT3,
SLC2A3 |
Illness | Cancer | Brain carcinoma |
clinical malignant and normal tissue samples, meningioma, glioma, ependymoma |
immunohi stochemist ry, autoradiog raphy |
increase of mRNA and protein expression, no or low expression in normal tissue |
mRNA expression suggested as a marker of aggressive biologic potential and major factor in tumor progression, potential targets for future therapy |
[113,151,155,177] |
GLUT3,
SLC2A3 |
Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples, tumor and adjacent normal breast tissues samples, benign and malignant cell line, breast cancer cell lines MCF-7, MDA-468, and ZR-75-1 |
immunocy tochemistr immunobl otting, Deoxyglu cose and Fructose uptake, RT-PCR, Western blotting, immunohi stochemist ry |
expressed mRNA and protein in breast cancer samples, no reactivity reported in cell lines, not expressed in normal mammary tissue, increase of mRNA, protein expression and activity by progesteron e and estrogen treatment |
[110,107,119,157,173,177] | |
GLUT3,
SLC2A3 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples, normal colon, benign colon adenomas and colorectal carcinoma tissue samples, normal and colon cancer cells transplanted in nude mice, invasive tubular carcinoma |
RT-PCR, Northern blotting |
Inconsiste nt results reported -mRNA expression similar in cancer and normal tissue, also increase of expression and activity in SNU-C5 tumors, or not expressed in normal tissue |
[128,164,177] | |
GLUT3,
SLC2A3 |
Illness | Cancer | Gastric carcinoma |
clinical tumor tissue samples |
immunohi stochemist ry, RT- PCR |
increase of mRNA and protein expression |
[115,127] | |
GLUT3,
SLC2A3 |
Illness | Cancer | Head and neck carcinoma |
clinical tumor tissue samples, head and neck squamous cell carcinoma, tissue of head and neck tumors, adjacent mucosa, and normal mucosa samples |
immunohi stochemist ry |
expression of mRNA and protein |
Inconsistent results reported - no association, or high gene expression level associated with an increased incidence of lymph node metastases |
[130,132] |
GLUT3,
SLC2A3 |
Illness | Cancer | Kidney carcinoma |
clinical tumor tissue samples, kidney surgical samples, clear cell RCC, papillary RCC, chromophobe RCC and oncocytoma tumors |
RT-PCR | mRNA expression in tumor cells as expressed in normal tissue |
[161] | |
GLUT3,
SLC2A3 |
Illness | Cancer | Laryngeal carcinoma |
clinical tumor tissue samples, biopsy samples of squamous cell carcinoma (SCC) of the larynx |
immunohi stochemist ry |
mRNA expressed |
associated with poor survival of patients |
[174] |
GLUT3,
SLC2A3 |
Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissue samples, non- small cell lung cancer (NSCLC) tissue samples, adenocarcino ma, mesothielom a |
immunohi stochemist ry, RT- PCR |
Inconsiste nt results reported -increase of mRNA, protein expression and activity, also low or no expression reported, not expressed in normal tissue |
suggested as a significant poor prognosis indicator in cases of NSCLC |
[109,115,136,137,138,139,151, 177] |
GLUT3,
SLC2A3 |
Illness | Cancer | Ovarian carcinoma |
clinical malignant and normal tissue samples |
immunohi stochemist ry |
Inconsiste nt results reported -increase of protein expression or no expression, not expressed in normal tissue |
[115,127] | |
GLUT3,
SLC2A3 |
Illness | Cancer | Pancreatic carcinoma |
clinical malignant and normal tissue samples, insulinomas, glucagonoma s and their lymph node metastases, gastrinoma, adenocarcino ma |
Northern blotting, RT-PCR, immunohi stochemist ry |
Inconsiste nt results reported – mRNA and protein expression, also low expression in tumor tissue and not expressed in normal tissue |
[152,177] | |
GLUT3,
SLC2A3 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
clinical samples, primary syncytotroph oblast cells, BeWo choriocarcino ma cells and human placental villous tissue explants |
immunobl otting, Northern blotting |
increase of mRNA, protein expression and activity |
expression may be of prognostic significance for hypoxic tumors |
[168,170,172] |
GLUT4,
SLC2A4 |
Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples, tumor and adjacent normal breast tissues samples, benign and malignant cell line, breast cancer cell lines MCF-7, MDA-468, and ZR-75-1 |
immunocy tochemistr y, immunobl otting, Deoxyglu cose and Fructose uptake, RT-PCR, Western blotting, immunohi stochemistry |
expression of mRNA and protein in breast cancer tissue and cell lines, very low expression, increase of mRNA, protein expression and activity by progesteron e and estrogen treatment, not expressed in normal breast tissue |
[110,119,157,177] | |
GLUT4,
SLC2A4 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples, normal and colon cancer cells transplanted in nude mice, invasive tubular carcinoma |
RT-PCR, Northern blotting |
very weak or no expression in colon cancer tumors, expressed in invasive tubular carcinoma, not expressed in normal tissue |
[164,177] | |
GLUT4,
SLC2A4 |
Illness | Cancer | Gastric carcinoma |
clinical tumor tissue samples |
immunohi stochemist ry, RT- PCR |
increase of mRNA e xpression |
[127,151] | |
GLUT4,
SLC2A4 |
Illness | Cancer | Kidney carcinoma |
clinical tumor tissue samples, kidney surgical samples, renal cell carcinoma (RCC), chromophobe RCC and oncocytoma tumors, papillary RCC, clear cell RCC |
RT-PCR | expressed in normal kidney tissue, in chromopho be RCC cells mRNA expression increased, in papillary RCC mRNA expression was as expressed in normal tissue, in clear cell RCC mRNA expression decreased |
suggested that high-affinity GLUTs might have a major role in enhanced glucose uptake in kidney tumors |
[161] |
GLUT4,
SLC2A4 |
Illness | Cancer | Lung carcinoma |
clinical tumor tissue samples, non- small cell lung cancer tissue samples |
immunohi stochemist ry, RT- PCR |
low or no expression, not expressed in normal tissue |
[138,139,177] | |
GLUT4,
SLC2A4 |
Illness | Cancer | Lymphoid carcinoma |
clinical tumor and normal tissue samples, Non-Hodgkin’s lymphoma biopsies and normal spleen samples |
immunohi stochemist ry |
low expression in tumor tissue, not expressed in normal spleen |
[177] | |
GLUT4,
SLC2A4 |
Illness | Cancer | Ovarian carcinoma |
clinical malignant and normal tissue samples, borderline, benign epithelial tumor |
immunohi stochemist ry |
increase of protein expression or no expression, absent in benign ovarian epithelial tumors, progressively more staining shown in invasive tumors as compared to borderline tumors, not expressed in normal tissue |
suggested as clinically useful prognostic information in patients with ovarian carcinoma |
[149,177] |
GLUT4,
SLC2A4 |
Illness | Cancer | Pancreatic carcinoma |
clinical malignant and normal tissue samples |
Northern blotting, Western immunobl otting, RT-PCR |
decrease of mRNA expression |
[142,151] | |
GLUT4,
SLC2A4 |
Physiologic al condition |
Exercise | Physical exercise |
transgenic mice gastrocnemiu s muscles samples |
Northern blotting |
increase of mRNA and protein expression |
[92] | |
GLUT5,
SLC2A5 |
Illness | Cancer | Brain carcinoma |
clinical tumor and normal tissue samples, choroid plexus papilloma, ependymoma |
immunohi stochemist ry |
weak expression, no expression in normal tissue |
[177] | |
GLUT5,
SLC2A5 |
Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples, breast cancer tissues samples, adjacent normal breast tissue, benign and malignant cell line, breast cancer cell lines MCF-7 and MDA-468 |
immunocy tochemistr y, immunobl otting, Fructose uptake, in situ RT- PCR |
expressed in breast cancer tissues and cell lines, increase of expression in ductal invasive carcinoma, not expressed in normal breast tissue, expressed in myoepitheli al cells |
suggested to be related to the neoplastic state in breast cancer cell lines MCF-7 and MDA-468, protein levels decreased with invasive potential |
[107,119,157,173,177] |
GLUT5,
SLC2A5 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor tissue samples, invasive tubular carcinoma |
RT-PCR, Northern blotting |
expressed in colon cancer tumors, expressed in normal tissue |
[177] | |
GLUT5,
SLC2A5 |
Illness | Cancer | Kidney carcinoma |
clinical tumor tissue samples, kidney surgical samples, renal cell carcinoma (RCC), chromophobe RCC and oncocytoma tumors, clear cell RCC and papillary RCC |
RT-PCR |
Inconsiste nt results reported -mRNA expression in tumor cells as expressed in normal tissue, or decrease of mRNA expression in tumor cells, expressed in normal tissue |
[161] | |
GLUT5,
SLC2A5 |
Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples, hepatocellula r carcinoma (HCC) |
immunohi stochemist ry |
weak expression, expressed in normal tissue |
[177] | |
GLUT5,
SLC2A5 |
Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissue samples, mesothielom a |
immunohi stochemist ry |
low expression, not expressed in normal tissue |
[177] | |
GLUT5,
SLC2A5 |
Illness | Cancer | Uterus carcinoma |
clinical tumor and normal tissue samples, leimyeoma |
immunohi stochemist ry |
expressed in tumor tissue, not expressed in normal tissue |
[177] | |
GLUT5,
SLC2A5 |
Illness | Diabetes | Diabetes, type II |
clinical samples, diabetic muscle cells |
RT-PCR, immunobl otting, immunohi stochemist ry |
increase of mRNA expression |
[91] | |
GLUT6,
SLC2A6 |
Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples |
immunocy tochemistr y, immunobl otting, Fructose uptake, immunohi stochemist ry |
weak expression in breast cancer tissues, not expressed in normal breast tissue |
[177] | |
GLUT6,
SLC2A6 |
Illness | Cancer | Pancreatic carcinoma |
clinical tumor and normal tissue samples, adenocarcino ma |
immunohi stochemist ry |
low expression in tumor tissue, not expressed in normal tissue |
[177] | |
GLUT6,
SLC2A6 |
Illness | Cancer | Uterus carcinoma |
clinical tumor and normal tissue samples, leimyeoma |
immunohi stochemist ry |
expressed in tumor tissue, not expressed in normal tissue |
[177] | |
GLUT9,
SLC2A9 |
Illness | Cancer | Kidney carcinoma |
clinical tumor tissue samples, kidney surgical samples, renal cell carcinoma (RCC), clear cell RCC, chromophobe RCC and oncocytoma tumors, papillary RCC |
RT-PCR | mRNA expression in tumor cells as expressed in normal tissue, decrease of mRNA expression in tumor cells, expressed in normal tissue |
[161] | |
GLUT9,
SLC2A9 |
Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples, hepatocellula r carcinoma (HCC) |
immunohi stochemist ry |
weak expression, expressed in normal tissue |
[177] | |
GLUT9,
SLC2A9 |
Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissue samples, mesothielom a |
immunohi stochemist ry |
low expression, expressed in normal tissue |
[177] | |
GLUT9,
SLC2A9 |
Illness | Cancer | Skin carcinoma |
clinical tumor and normal tissue samples, melanoma biopsies |
immunohi stochemist ry |
low expression in tumor tissue, not expressed in normal tissue |
[177] | |
GLUT9,
SLC2A9 |
Illness | Cancer | Thyroid carcinoma |
clinical tumor and normal tissue samples, thyroid carcinoma, papillary carcinoma biopsies |
immunohi stochemist ry, RT- PCR |
expressed in papillary carcinoma biopsies, not expressed in normal breast tissue |
[177] | |
GLUT10
SLC2A1 0 |
Illness | Cancer | Kidney carcinoma |
clinical tumor tissue samples, kidney surgical samples, renal cell carcinoma (RCC), chromophobe RCC and oncocytoma tumors, clear cell RCC and papillary RCC |
RT-PCR | decrease of mRNA expression in tumor cells, or mRNA expression in tumor cells as expressed in normal tissue |
[161] | |
GLUT12, SLC2A1 2 |
Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples, breast cancer and benign tumor tissues samples, breast cancer cultured cells |
immunohi stochemist ry, RT- PCR |
increase of expression in breast cancer cell lines, low or no expression in benign tumor |
suggested as novel method for detection and treatment of breast cancer |
[163,173] |
GLUT12,
SLC2A1 2 |
Illness | Cancer | Kidney carcinoma |
clinical tumor tissue samples, kidney surgical samples, renal cell carcinoma (RCC), chromophobe RCC and oncocytoma tumors, clear cell RCC and papillary RCC |
RT-PCR | decrease of mRNA expression in tumor cells as expressed in normal tissue |
[161] | |
GLUT12,
SLC2A1 2 |
Illness | Cancer | Prostate carcinoma |
clinical prostate carcinoma tissue samples, prostate cancer cells and cultured cancer cell lines LNCaP, C4, C4-2, and C4-2B using primers to amplify GLUT12, benign prostatic hyperplasia |
RT-PCR, Western immunobl otting, Northern blotting |
increase of mRNA and protein expression, expressed in human prostate tumors, low or no expression in normal cells, not expressed in benign prostatic hyperplasia , mRNA expressed in cancer cell lines |
suggested as novel method for detection and treatment of prostate cancer |
[72,173,176] |
LAT1,
SLC7A5 |
Illness | Cancer | Bladder carcinoma |
clinical tumor tissue samples,T24 human bladder carcinoma cells |
RT-PCR, Northern blot, immunofl uorescenc e |
increase of mRNA expression, protein level and activity |
[97] | |
LAT1,
SLC7A5 |
Illness | Cancer | Esophageal carcinoma |
esophageal adenocarcino ma cell lines, Barrett’s adenocarcino ma cell lines, esophageal squamous- cell carcinoma cell lines, esophagus endoscopy tissue samples, non- cancerous esophageal mucosa |
RT-PCR, Western immunobl otting, immunohi stochemist ry |
increase of mRNA and protein expression comparing to non- cancerous esophageal mucosa |
[103,105] | |
LAT1,
SLC7A5 |
Illness | Cancer | Head and neck carcinoma |
head and neck squamous cell carcinoma cell line, Hep-2 |
Western immunobl otting |
increase of expression |
suggested that combination of an antitumor agent with inhibitors of LAT1 would be beneficial to the cancer therapy |
[101,102] |
LAT1,
SLC7A5 |
Illness | Cancer | Oral carcinoma |
KB oral epidermoid carcinoma cells, oral squamous cell carcinoma and its precursor lesions, human osteoblast cells and Saos2 human osteogenic sarcoma cells |
RT-PCR, Western immunobl otting, immunohi stochemist ry |
increase of mRNA and protein expression |
proposed as more specific indicator of tumor progression, suggested that specific inhibition of LAT1 in tumor cells might be a new rationale for antitumor therapy |
[98,99,100] |
LAT2,
SLC7A8 |
Illness | Cancer | Osteosarco ma |
human osteoblast cells and Saos2 human osteogenic sarcoma cells |
RT-PCR, Western immunobl otting |
very low mRNA and protein expression |
[99] | |
LRP,
VALUT1, MVP |
Illness | Cancer | Bladder carcinoma |
clinical tumor and normal tissue samples, transitional cell carcinoma |
immunohi stochemist ry, RT- PCR |
high mRNA and protein expression, mRNA level was significantl y greater in normal bladder tissue |
significantly associated with a worse response to neoadjuvant chemotherapy (NACT) and a decreased probability of bladder preservation |
[401,421] |
LRP,
VALUT1, MVP |
Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples, primary breast cancers |
immunohi stochemist ry, RT- PCR |
expression of mRNA and protein |
Inconsistent results reported – suggested that may play a role in anthracycline resistance, expression is significantly associated with nodal metastases, reported not to relate to the relapse or prognosis in patients treated with doxorubicin- based chemotherapy |
[344,346,378,398] |
LRP,
VALUT1, MVP |
Illness | Cancer | Gastric carcinoma |
clinical stomach tumor and normal tissue samples, primary gastric cardiac adenocarcino ma |
immunohi stochemist ry |
increase of protein expression compared to normal tissue |
level of expression appears to correlate with the degree of differentiation, well-differentiated carcinomas contained significantly higher level of expression, expression not associated with the invasion degree and lymph node metastases |
[349,350,352] |
LRP,
VALUT1, MVP |
Illness | Cancer | Leukemia | clinical tumor tissue samples, acute lymphocytic (lymphoblasti c) leukemia (ALL), acute myeloid leukemia (AML), bone marrow samples |
RT-PCR, flow cytometric assays, immunohi stochemist ry |
Inconsiste nt results reported – increase of mRNA and protein expression, also no difference in LRP expression levels between initial or relapsed patients |
Inconsistent results reported – related to worsened eventfree survival with resistance to induction chemotherapy and the relative risk of relapse, might contribute to drug resistance in B-lineage ALL, also no correlation between LRP expression and clinical outcome and drug resistance, suggested lack of clinical significance in AML but that might contribute to drug resistance in children with ALL |
[345,354,355,356,357,377,378, 379] |
LRP,
VALUT1, MVP |
Illness | Cancer | Liver carcinoma |
clinical tumor tissue samples, hepatocellula r carcinoma (HCC), HepG2 cell line |
RT-PCR, Western immunobl otting |
increase of mRNA expression in tumor tissue compared to normal tissue |
[397] | |
LRP,
VALUT1, MVP |
Illness | Cancer | Lymphoid carcinoma |
clinical samples, T/NK-cell lymphomas, nasal NK/T cell lymphoma |
immunohi stochemist ry |
expression of protein |
[399,400] | |
LRP,
VALUT1, MVP |
Illness | Cancer | Ovarian carcinoma |
clinical tumor tissue samples, advanced ovarian carcinoma |
immunohi stochemist ry |
increase of mRNA expression |
suggested as indicator of poor response to standard chemotherapy |
[376,378] |
LRP,
VALUT1, MVP |
Illness | Cancer | Prostate carcinoma |
clinical tumor tissues samples |
immunohi stochemistry |
increase of expression in tumor tissue with increased pathology |
[315] | |
LRP,
VALUT1, MVP |
Illness | Cancer | Tongue carcinoma |
clinical tumor tissue samples, squamous cell carcinoma |
immunohi stochemist ry |
expression of protein |
[351] | |
LRP,
VALUT1, MVP |
Illness | Cancer | Wilms’ tumor |
clinical tumor tissue samples, nephroblasto ma |
immunohi stochemist ry, RT- PCR, tissue microarray technique |
Inconsiste nt results reported – expression of mRNA and protein, low or no expression in normal tissue, also no expression of protein in tumor samples reported |
significant relationships between expression and chemotherapeutic pre-treatment of tumors and tumor stage found, expression proposed as positive indicator |
[404,418,420] |
LRP,
VALUT1, MVP |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
HepG2 human hepatocellula r carcinoma cells, gas mixture and CoCl(2) induced hypoxia |
RT-PCR, Western immunobl otting |
increase of mRNA expression and protein level |
proposed as one of the causes for the formation of multidrug resistance in HepG2 human hepatocellular carcinoma cell line |
[183] |
MCT1,
SLC16A 1 |
Illness | Inflamm ation |
Intestinal inflammatio n |
clinical tumor tissue samples, colonic tissues collected from patients with IBD or healthy controls |
RT-PCR, Western immunobl otting, immunohi stochemist ry, Butyrate uptake |
decrease of mRNA expression and protein level |
[190] | |
MCT4,
SLC16A 3 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
HeLa and COS cells, CoCl(2) induced hypoxya |
RT-PCR, Western immunobl otting |
increase of mRNA expression, increase of protein level |
[186] | |
MDR1,
P-glycopro tein, P gP, ABCB1 |
Demographi c factor |
Age | Adults, age range 21-27 years and age range 59-68 years |
healthy volunteers, CD3-positive leukocytes |
[(11)C]-Verapamil (R)- BBB distributio n, positron emission tomography |
decreased activity during aging |
[79] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Demographi c factor |
Age | Children, age range 1 to 17 years |
clinical samples, duodenal biopsies samples |
RT-PCR | no statistical relation with age in mRNA expression |
[62] | |
MDR1,
P-glycopro tein, P gP, ABCB1 |
Illness | Cancer | Adrenal carcinoma |
clinical tumor tissue samples, pheochromoc ytoma, adrenocortica l carcinoma, neuroblastom a |
immunohi stochemist ry, Slot Blot Analysis |
increase of mRNA expression, high protein level detected, expressed in normal tissue |
[313,314,326,364] | |
MDR1,
P- glycopro tein, P gp, ABCB1 |
Illness | Cancer | Bladder carcinoma |
clinical tumor tissue samples, bladder transitional cell carcinomas, tumor cell lines, vincristine- resistant cell line T24/VCR |
immunohi stochemist ry, flow cytometry, RT-PCR |
low or high protein expression detected, low expression in normal tissue, increase of mRNA and protein expression in T24/VCR cells |
correlated with shorter progression-free survival but not with overall survival |
[314,327,328,329,330,401,421] |
MDR1,
P-glycoprotein, P- gP ABCB1 |
Illness | Cancer | Breast carcinoma |
clinical tumor and normal tissue samples, breast-cancer cell lines, primary breast cancers tumor tissue samples, invasive breast carcinomas |
immunohi stochemist ry, RT- PCR, Rh l23 dye-efflux assay, Slot Blot Analysis |
low or no mRNA and protein expression and activity in primary tumor tissues and breast carcinoma cells, no significant increase of mRNA expressed in tissue samples from patients clinically treated with anthracycli nes |
Inconsistent results reported-no evidence of significant activity of the P- gp pump, no correlation between clinical response and MDRl/P-Gp mRNA expression, also suggests that MDR1 is an important predictor of poor prognosis in breast cancer patients receiving chemotherapy as first-line treatment for recurrent disease, expression is significantly associated with nodal metastases, associated strongly with higher histological grade (grade III), also no association was shown between MDR-1 P-gp expression and survival times |
[,313,314,330,342,343,344,346, 347,360,367,398] |
MDR1,
P-glycopro tein, P gP, ABCB1 |
Illness | Cancer | Childhood carcinoma |
clinical tumor tissue samples, neuroepitheli oma, Ewing sarcoma, neuroepitheli oma |
Slot Blot Analysis |
low increase of mRNA expression in some samples, low expression in normal tissue |
[364] | |
MDR1,
P- glycopro tein, P gp, ABCB1 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples, normal colon mucosa, tumor and adjacent non- cancerous tissue samples, tumor cell lines, parental cells and Pgp- overexpressin g doxorubicin-resistant SW620R cells from SW620 human colon cancer cells, Human colorectal cancer cells (Caco-2) |
immunobl otting, immunohi stochemist ry, RT- PCR, Slot Blot Analysis |
increase of mRNA expression and protein in tumor tissues, decrease of mRNA expression in tumor tissue compared to non- cancerous regions, expressed in normal tissue, expression of mRNA in cell lines |
level of expression appears to correlate with the degree of differentiation, well- differentiated carcinomas contained significantly higher level of expression |
[,268,314,317,322,326,330,358, 364,423] |
MDR1,
P- glycopro tein, P gp, ABCB1 |
Illness | Cancer | Eye cancer | clinical tumor tissue samples, retinoblastom a |
immunohi stochemist ry |
expression of mRNA and in tumor tissues |
no statistically significant relationship between the expressions and tumor differentiation, presence of tumor invasion or treatment with chemotherapy |
[371] |
MDR1,
P- glycopro tein, P gP, ABCB1 |
Illness | Cancer | Gallbladder carcinoma |
Mz-ChA-1 cells derived from gallbladder adenocarcino ma |
RT-PCR, immunobl otting, immunofl uorescenc e microscop y |
expression of mRNA |
[402] | |
MDR1,
P- glycopro tein, P gp, ABCB1 |
Illness | Cancer | Gastric carcinoma |
clinical tumor and normal tissue samples, gastric cardiac adenocarcino ma, |
immunohi stochemist ry |
increase of protein expression compared to normal tissue, low expression in normal tissue |
expression was closely related with clinicopathologic staging, the level of expression appears to correlate with the degree of differentiation, well-differentiated colorectal carcinomas contained significantly higher level |
[314,349,352,358] |
MDR1,
P- glycopro tein, P gp, ABCB1 |
Illness | Cancer | Insulinoma | clinical tumor tissue samples |
immunohi stochemist ry |
high protein level detected |
[314] | |
MDR1,
P- glycopro tein, P gP, ABCB1 |
Illness | Cancer | Large intestine tumor |
clinical tumor tissue samples |
RT-PCR, Western immunobl otting |
no difference in mRNA and protein expression between normal and tumor tissue |
[63] | |
MDR1,
P-glycopro tein, P- gP ABCB1 |
Illness | Cancer | Leukemia | clinical tumor and normal tissue samples, acute lymphocytic (lymphoblasti c) leukemia (ALL), acute nonlymphocy tic leukemia (ANLL), tumor cell lines, lymphoblasti c leukemia, acute myeloid leukemia (AML), bone marrow aspirates or peripheral blood were collected from AML patients, HL60 cell line, HL6O/DOX cells, K562/VCR cells |
RT-PCR, flow cytometric assays, Rh l23 and Di(OC)2 efflux assay, Slot Blot Analysis, calcein- AM uptake, MultiDrug Quant assay kit, immunohi stochemist ry, Southern blotting, DOX uptake and efflux, immunobl otting |
increase of mRNA, protein expression and activity, low or high expression in some samples, low expression of mRNA level in HL6O/DOX cells similar to that of the parent HL60 cells with no protein detected, expression of mRNA and protein in HHT90 cell lines, expression of protein in PC13, PC13 2-2, HHT90, HL60, and HL60/MRP cell lines |
Inconsistent results reported – great variability in mRNA expression in AML patient samples, confirmed the clinical relevance of expression and functional CsA- inhibited drug efflux in AML and in pediatric ALL patients, associated with poor treatment outcome in AML patients, P-gp function was a prognostic factor only in AML patients receiving Daunorubicin or Idarubicin, because of diversity of the results it was concluded that clinical importance of P- gp in childhood ALL remains unclear, functional activity is a more sensitive predictor of chemoresistance than P-gp surface expression |
[326,330,345,354,355,356,357, 364.377.379,380,381,391,392, 406,408.409.410,411] |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Illness | Cancer | Lipoma | clinical tumor and normal tissue samples |
RT-PCR | increase of mRNA expression in some samples |
[330] | |
MDR1,
P-glycopro tein, P gP, ABCB1 |
Illness | Cancer | Liver carcinoma |
clinical tumor and normal tissue samples, hepatocellula r carcinoma (HCC) |
RT-PCR, Slot Blot Analysis, immunohi stochemist ry, Western immunobl otting |
increase of mRNA expression, or expression as in normal tissue |
could be up- regulated by anti- cancer agents in vitro |
[326,364,396,397] |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Illness | Cancer | Lung carcinoma |
clinical tumor and normal tissue samples, adenocarcino ma, non- small cell and small cell lung cancer cell lines |
immunohi stochemist ry, RT- PCR, Slot Blot Analysis, Western immunobl otting, |
Inconsisten t results reported - low expression of mRNA and protein in clinical samples, no or expression only in some cell lines, expressed in normal tissue |
overexpression related to acquired multidrug resistance in vivo |
[314,318,320,321,326,320,330, ,331,364,368] |
MDR1,
P- glycopro tein, P gp, ABCB1 |
Illness | Cancer | Lymphoid carcinoma |
clinical tumor tissue samples, primary tumors, 44 T- cell lymphomas, indolent non-Hodgkin’s lymphoma, resistant leukemia cell sublines, T/NK-cell lymphomas |
immunobl otting, immunohi stochemist ry, RT- PCR, Northern blotting, Rh123 dye-efflux assay, Slot Blot Analysis |
increase of mRNA, protein expression and activity in leukemic cells, low expression in normal lymphocyte s |
concluded that assays tested are suitable for evaluating P-gp expression and function in clinical samples |
[287,326,330,341,342,364,399] |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Illness | Cancer | Neuroblasto ma cancer |
clinical tumor tissue samples, primary neuroblastom a, cultured cell lines, |
Western immunobl otting, RT-PCR |
expression of mRNA and protein |
expression demonstrated no prognostic significance |
[374,375,414,415] |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Illness | Cancer | Ovarian carcinoma |
clinical tumor and normal tissue samples, advanced o varian carcinoma |
RT-PCR, Slot Blot Analysis |
increase of mRNA expression in some samples, low expression in normal tissue |
low-level expression of mRNA correlates with clinical resistance, no association was found between expression and response to chemotherapy and survival |
[330,331,364,376] |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Illness | Cancer | Pancreatic carcinoma |
clinical tumor tissue samples |
RT-PCR | increase of mRNA expression in some samples |
[326] | |
MDR1,
P- glycopro tein, P gp, ABCB1 |
Illness | Cancer | Penile carcinoma |
penile squamous cell carcinoma |
immunohi stochemist ry |
expression of protein |
[327] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Illness | Cancer | Prostate carcinoma |
clinical tumor and normal tissue samples, prostate adenocarcino mas, cancer cell lines |
immunohi stochemistry Western immunobl otting, Slot Blot Analysis |
lower expression of protein in tumor tissue than normal tissue, or no protein expression, low expression in normal tissue |
[291,303,315 ,348,364] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Illness | Cancer | Renal carcinoma |
clinical tumor tissue samples, renal cell carcinomas (RCC), clear cell type |
immunohi stochemist ry, RT- PCR |
increase of mRNA expression, high protein level detected |
[314,326,327,361] | |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Illness | Cancer | Sarcoma | clinical tumor and normal tissue samples, osteosarcoma, chondrosarco ma, soft tissue sarcomas, Ewing’s sarcoma |
RT-PCR | increase of mRNA expression |
[330] | |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Illness | Cancer | Tongue carcinoma |
clinical tumor tissue samples, squamous cell carcinoma |
immunohi stochemist ry |
expression of protein, expression ratios in post- chemothera py cases were higher |
relevance with drug resistance |
[351] |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Illness | Cancer | Wilms’ tumor |
clinical tumor tissue samples, nephroblasto ma |
immunohi stochemist ry |
no expression of protein |
[404] | |
MDR1,
P-glycopro tein, P gP, ABCB1 |
Demographi c factor |
Gender | Male, Female |
human liver samples |
RT-PCR, Western immunobl otting, immunohi stochemist ry |
no significant differences between men and women in mRNA level |
[3] | |
MDR1,
P-glycopro tein, P gP, ABCB1 |
Physiologic al condition |
Hyperthe rmia |
Temperatur e elevation |
ADM- resistant MCF-7 breast cancer cell line |
RT-PCR, flow cytometry |
decrease of protein level in cell membranes in co- treatment with INF- alpha, and Verapamil |
suggested that hyperthermia may be exploited in clinical cancer chemotherapy |
[93] |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Physiologic al condition |
Hyperthe rmia |
Temperatur e elevation |
human prostate cancer cell line DU-145, multicellular prostate tumor spheroids |
RT-PCR, immunohi stochemist ry, Doxorubic in uptake, immunopr ecipitation |
increase of mRNA expression, increase of protein level and activity |
[209,211] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Therapeutic condition |
Hypothe rmia |
Temperatur e decrease |
LLC-PK1 and LLC- GA5- COL150 cells |
Digoxin, Quinidine, and Tetracycli ne transport |
decrease of activity |
[195] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
cultured human cervical cancer cell line HeLa, Hepa1 tumor spheroids, human lung adenocarcino ma A549 cells, HepG2 human hepatocellula r carcinoma cells, human ovarian cancer cells, gas mixture and CoCl(2) induced hypoxia |
RT-PCR, Western immunobl otting |
increase of mRNA expression and protein level |
proposed as one of the causes for the formation of multidrug resistance in HepG2 human hepatocellular carcinoma and human ovarian cancer cells |
[181,182,183,184,169] |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Illness | Inflamm ation |
Inflammato ry bowel disease, Crohn’s disease |
clinical samples, duodenal biopsies samples |
RT-PCR | increase of mRNA expression |
[61] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Illness | Inflamm ation |
Intestinal inflammation |
intestinal mucosal biopsies samples from patients with Crohn’s disease, diverticulitis, collagenous colitis and healthy controls |
RT-PCR, Western immunobl otting, immunohi stochemist ry |
decrease of mRNA expression and protein level |
[189] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Illness | Liver disease |
Acetaminop hen overdoses |
injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplification assay, immunohi stochemist ry |
increase of protein level |
[205] | |
MDR1,
P-glycopro tein, P gp, ABCB1 |
Illness | Liver disease |
Primary biliary cirrhosis |
injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplification assay, immunohi stochemist ry |
increase of mRNA expression, increase of protein level |
[205] | |
MDR1,
P-glycoprotein, P gp, ABCB1 |
Physiologic al condition |
Oxidativ e stress |
Reactive oxygen species |
hydrogen peroxide exposure, multicellular prostate tumor spheroids overexpressing the ROS-generating enzyme Nox- 1, human prostate cancer cell line DU-145, multicellular prostate tumor spheroids with prooxidants |
RT-PCR, immunohi stochemist ry, Doxorubic in uptake |
decrease of protein level and activity in large prostate tumor spheroids |
[181,202,203,210] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Bladder carcinoma |
the cisplatin- resistant bladder carcinoma cell lines T24/DDP7 and T24/DDP1O, doxorubicin- resistant T24/ADM-1 and T24/ADM-2 cells |
immunohi stochemist ry, RNase protection assays, Southern blotting |
low increase of mRNA and protein expression, expressed in normal tissue, increase of mRNA expression in T24/AD M cells |
correlated with a higher response and a higher probability of bladder preservation following neoadjuvant chemotherapy (NACT) |
[318,329,362,401,421] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Brain carcinoma |
clinical tumor tissue samples, glial cell tumors, astrocytoma, anaplastic astrocytoma, glioblastoma cell line A172 |
immunohi stochemist ry, RT- PCR, Northern blotting, RNase protection assay, Western immunobl otting, LTC4 uptake |
increase of expression of mRNA and protein in tumor tissue, expression of mRNA and protein in untreated cells, transient increase of mRNA, protein expression and activity in cell treated by ACNU, low expression in normal tissue |
suggested to contribute in development of MRP-related multidrug resistance |
[316,318,353] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples, primary breast cancers, invasive breast carcinomas, breast cancer cell lines |
immunohi stochemist ry, RT- PCR |
Inconsiste nt results reported – low expression of mRNA and protein, also protein not detected |
Inconsistent results reported – suggested that may play a role in anthracycline resistance, but not in CMF treated patients, suggested to be of prognostic significance in the subgroups of patients with the more favorable prognosis, i.e. patients with small tumors and node-negative patients, as well as in the setting of adjuvant systemic chemotherapy, also no evidence linking this protein to clinical drug resistance |
[344,359,360,367,393,394,398] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor tissue samples, tumor and adjacent non- cancerous tissue samples, primary colorectal carcinomas, the cisplatin- resistant colon carcinoma cell lines HCT8/DDP, parental cells and Pgp-overexpressin g doxorubicin- resistant SW620R cells from SW620 human colon cancer cells |
immunohi stochemist ry, RT- PCR, RNase protection assays |
mRNA of expression in tumor tissue and non- cancerous regions, expressed in normal tissue, low increase of mRNA expression in HCT8 cell lines, expression of mRNA in cancer cells |
appear not to be related to the age and sex of the patients, localization of the primary tumor, histological grade, tumor size, lymph node metastases, distant metastases and tumor stage |
[317,318,322,363,366] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Eye cancer | clinical tumor tissue samples, retinoblastom a |
multilayer immunope roxidase staining, immunohi stochemist ry |
expression of mRNA in tumor tissues |
no statistically significant relationship between expression and tumor differentiation, presence of tumor invasion or treatment with chemotherapy |
[370,371] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Gallbladder carcinoma |
Mz-ChA-1 cells derived from gallbladder adenocarcino ma |
RT-PCR, immunobl otting, immunofl uorescenc e microscop y |
expression of mRNA, also mRNA not detected |
[402] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Gastric carcinoma |
clinical tumor and normal tissue samples, primary gastric cardiac adenocarcino ma |
immunohi stochemist ry, RT- PCR, Southern hybridizati on |
increase of mRNA and protein expression compared to normal tissue |
level of expression appears to correlate with the degree of differentiation, well- differentiated carcinomas contained significantly higher level of expression, expression not associated with the invasion degree and lymph node metastases |
[350,352,372,373] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Hepatic carcinoma |
clinical tumor and correspondin g normal liver tissue samples |
immunobl otting, RT-PCR, immunohi stochemist immunofl uorescenc e microscop y |
low or no expression of mRNA and protein, low or no expression in normal tissue |
[323] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Leukemia | clinical tumor tissue samples, acute lymphocytic (lymphoblasti c) leukemia (ALL), doxorubicin- resistant sublines of the leukemia cancer cell line HL6O/ADR, parental cells and MRP-overexpressing multidrug-resistant HL60R cells from HL60 human promyelocytic leukemia cells, acute myeloid leukemia (AML), bone marrow aspirates or peripheral blood were collected from AML patients, HL60/DOX cells, K562/VCR cells |
immunobl otting, RNase protection assays, immunohi stochemist ry, RT- PCR, flow cytometric assays, DL- Buthionin e (S,R)- Sulfoximi ne (BSO) efflux assay, effect of Probenecid on calcein efflux, calcein-AM and Rh123 assays, MultiDrug Quant assay kit, Southern blot analysis, DOX uptake and efflux assay, immunobl otting |
increase of mRNA and protein expression, not expressed in parenteral cells, increase of mRNA expression in HL60/DOX cells, expression of protein in PC13, PC13 2-2, HL60, and HL60/MRP cell lines |
Inconsistent results reported - great variability in mRNA expression and suggested lack of clinical significance in AML patient samples, also suggested that it contributes to drug resistance in AML, or that does not seem to play a major role in multidrug resistance in childhood acute ALL, concluded that the activity had no prognostic impact and that did not correlate with prognostically unfavorable immunophenotyp e, white blood cell count or age, mainly involved in the resistance mechanism of the HL60/DOX cells, relapsed patients showed a higher expression, high expression has an unfavorable prognosis |
[45,318,322,345,354, 355,356,357,377,379,380,381, 391,406,408,409,410,411] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Liver carcinoma |
clinical tumor tissue samples, hepatocellula r carcinoma (HCC), HepG2 cell line |
RT-PCR, immunohi stochemist ry, Western immunobl otting |
increase of mRNA expression in tumor tissue compared with normal tissue |
may result in an aggressive tumor phenotype |
[396,397] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Lung carcinoma |
clinical tumor tissue samples, large cell carcinoma, non-small cell (NSCLC) and small cell lung cancer cell lines not selected for drug resistance, non-small cell lung cancer cell lines COR- L231R, and small cell lung cancer cell lines GLC4/ADR, doxorubicin- resistant sublines of the lung adenocarcino ma cell line MOR/R |
immunobl otting, RNase protection assays, Western immunobl otting, RT-PCR, Northern blotting |
increase of mRNA and protein expression, expressed in normal tissue, expression level of squamous- cell carcinomas was significantl y higher than that of adenocarci noma |
suggested as component of the multifactor multidrug resistance phenotype of lung cancer in some squamous- cell carcinomas of the lung, gene expression is related to the histopathology and prognosis in NSCLC, |
[318,319,320,321,363,369] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Lymphoid carcinoma |
clinical tumor tissue samples, T/NK-cell lymphomas, nasal NK/T cell lymphoma |
immunohi stochemist ry |
expression of protein |
[399,400] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Neuroblasto macarcinoma |
clinical tumor samples, primary neuroblastom a tumors, cultured cell lines, |
Western immunobl otting, RT-PCR, Southern blotting, Northern blotting |
increase of expression of mRNA and protein |
suggested to have role in the malignant, chemoresistant phenotype and to be powerful prognostic indicator for children with neuroblastoma, also suggested that positive MRP1 RNA expression at diagnosis has prognostic significance, but high drug resistance is conferred by mechanisms other than MRP1, proposed that inhibition may be a clinically relevant approach to improving patient outcome in this disease |
[374,375,414,415,416,417] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Ovarian carcinoma |
clinical tumor tissue samples, the cisplatin-resistant 2008 and the A2780 ovarian carcinoma cell lines, advanced ovarian carcinoma |
RNase protection assays, immunohi stochemist ry |
increase of mRNA expression, low expression in normal tissue |
no association was found between expression and response to chemotherapy and survival |
[318,376] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Pancreatic carcinoma |
clinical tumor tissue samples, pancreatic cancer cell lines |
reverse- transcripta se (RT)- PCR, RT- PCR, immunohi stochemist ry |
expression of mRNA in cell lines |
[395] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Prostate carcinoma |
clinical prostate tissues, parental cells and CDDP- resistant P/CDP6 cells derived from PC-3 human prostate cancer cells, cancer cell lines |
immunohi stochemist ry, RT- PCR, Western immunobl otting |
increase of mRNA and protein expression in tumor tissue, expressed in normal tissue, expression in cell lines |
increase of expression with increased pathology, may play a role in the development of drug resistance |
[291,302,315,322,325,348,417] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Renal carcinoma |
clinical tumor tissue samples, renal pelvic tumor, renal- cell carcinoma |
Southern blotting, immunohi stochemist ry |
expression of mRNA and protein |
[362] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Tongue carcinoma |
clinical tumor tissue samples, squamous cell carcinoma |
immunohi stochemist ry |
expression of protein, expression ratios in post-chemothera py cases were higher |
relevance with drug resistance |
[351] |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Ureter carcinoma |
clinical tumor tissue samples |
Southern blotting, immunohi stochemist ry |
expression of mRNA and protein |
[362] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Cancer | Wilms’ tumor |
clinical tumor tissue samples, nephroblasto ma |
immunohi stochemist ry, RT- PCR, tissue microarra y technique |
Inconsiste nt results reported – expression of mRNA and protein, also observed reduction in expression, high expression in normal tissue |
Inconsistent results reported - positive expression of MRP1 correlated with a lower probability of survival, but there was no evidence that higher levels of MRP1 at diagnosis conferred a worse prognosis,, higher expression of MRP1 does not always correlate with poor survival, expression proposed also as positive indicator |
[404,416,419,420] |
MRP1,
MRP, GS-X, ABCC1 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
human lung adenocarcino ma A549 cells, HepG2 human hepatocellula r carcinoma, human ovarian cancer cells, gas mixture |
RT-PCR, Western immunobl otting |
increase of mRNA expression, increase of protein level |
proposed as one of the causes for the formation of multidrug resistance in HepG2 human hepatocellular carcinoma and human ovarian cancer cells |
[182,183,184 |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Infection | Human T cell lymphotropi c/leukaemia virus type I, HTLV-I |
peripheral blood mononuclear cells, T lymphocytes from infected and control patients |
RT-PCR, Western immunobl otting |
decrease of mRNA expression, protein level and activity |
[95] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Liver disease |
Acetaminop hen overdoses |
clinical samples, injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplificati on assay, immunohi stochemist ry |
increase of mRNA expression |
[205] | |
MRP1,
MRP, GS-X, ABCC1 |
Illness | Liver disease |
Primary biliary cirrhosis |
clinical samples, injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplificati on assay, immunohi stochemist ry |
increase of mRNA expression, increase of protein level |
[205] | |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples, primary breast cancers tumor tissue samples, breast cancer cell lines |
RT-PCR, immunohi stochemist ry |
low expression of mRNA |
Inconsistent results reported - suggested that may play a role in anthracycline resistance, also no evidence linking this proteins to clinical drug resistance |
[344,394] |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor tissue samples, tumor and adjacent non- cancerous tissue samples, the cisplatin- resistant colon carcinoma cell lines HCT8/DDP and non- drug- selected cells, parental cells and Pgp- overexpressin g doxorubicin- resistant SW620R cells from SW620 human colon cancer cells |
immunohi stochemist ry, RT- PCR, Western immunobl otting |
increase of mRNA and protein expression in tumor tissues compared to non cancerous regions, increase of mRNA and protein expression in HCT8 cell lines, also no expression in normal tissue |
[317,318,322] | |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Epidermoid carcinoma |
KB-3-1 parental cell lines |
RNase protection assays, Western immunobl otting |
increase of mRNA and protein expression, no expression in normal tissue |
[318] | |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Gallbladder carcinoma |
clinical tumor tissue samples, Mz- ChA-1 cells derived from gallbladder adenocarcino ma |
RT-PCR, immunobl otting, immunofl uorescenc e microscop y |
expression of mRNA in cells and some tumor samples |
[402,403] | |
MRP2, cMOAT, ABCC2 | Illness | Cancer | Gastric carcinoma |
non-drug- selected cells |
immunohi stochemist ry, RT- PCR, Western immunobl otting |
expressed of mRNA and protein, expressed in normal tissue |
[317,318,322] | |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Head and neck carcinoma |
cisplatin- resistant head and neck cancer KB cell line |
fluorescen ce in situ hybridizati on |
increase of mRNA expression |
[322] | |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Hepatic carcinoma |
clinical tumor and correspondin g normal tissue samples |
immunobl otting, RT-PCR, immunohi stochemistry immunofl uorescenc e microscop y |
expression of mRNA and protein in tumor and in normal tissue |
suggested to contribute to the intrinsic MDR phenotype |
[323] |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Leukemia | parental cells and MRP- overexpressin g multidrug- resistant HL60R cells from HL60 human promyelocyti c leukemia cells, bone marrow aspirates or peripheral blood were collected from AML patients |
immunohi stochemist ry, RT- PCR, functional drug efflux |
expressed of mRNA and protein, expressed in normal tissue, expressed in parenteral cells, expressed of mRNA PC13, PC13 2-2, K562, HL60, and HL60/MRP cell lines |
great variability in mRNA expression in AML patient samples, relapsed patients showed a higher mRNA expression, high expression has an unfavorable prognosis |
[45,322,377,386,410, 411] |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Lung carcinoma |
non-small cell and small cell lung cancer cell lines not selected for drug resistance, parental lung adenocarcino ma cell line MOR/P, doxorubicin- resistant sublines of the non-small cell lung cancer cell lines SW1573/Sl and non- drug-selected cells |
immunohi stochemist ry, RNase protection assays, Western immunobl otting, RT-PCR |
increase of mRNA and protein expression, no expression in normal tissue |
little evidence to support or refute a role for the involvement in the drug resistance of lung cancer cells |
[318,319,320,322] |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Pancreatic carcinoma |
clinical tumor tissue samples, pancreatic cancer cell lines |
reverse- transcripta se (RT)- PCR, RT- PCR, immunohi stochemist ry |
expression of mRNA in cell lines, increase of mRNA and protein tumor tissue samples compared to normal tissue, protein not expressed in normal tissue |
may correlate to intrinsic and acquired resistance for CDDP in human pancreatic cancer |
[395] |
MRP2,
cMOAT, ABCC2 |
Illness | Cancer | Prostate carcinoma |
parental cells and CDDP- resistant P/CDP6 cells derived from PC-3 human prostate cancer cells |
immunohi stochemist ry, RT- PCR |
expressed of mRNA and protein, expressed in normal tissue |
[291,322] | |
MRP2,
cMOAT, ABCC2 |
Illness | Liver disease |
Cholecyst cholesterol lithiasis |
clinical samples, liver tissue samples |
RT-PCR, Western immunobl otting |
increase of mRNA and protein expression |
[90] | |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Breast carcinoma |
clinical tumor tissue samples, primary breast cancers tumor tissue samples, breast cancer cell lines |
RT-PCR, immunohi stochemist ry |
expression of mRNA |
no evidence linking the protein to clinical drug resistance |
[394] |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Cholangio carcinoma |
clinical tumor tissue samples |
RT-PCR, immunobl otting, immunofl uorescenc e microscop y |
high expression of mRNA |
suggested to contribute to the MDR phenotype, |
[402] |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor tissue samples, tumor and adjacent non- cancerous tissue samples, the cisplatin-resistant colon carcinoma cell lines HCT8/DDP |
immunohi stochemist ry, RT- PCR, immunobl otting, RNase protection assays, Northern blotting |
decrease of mRNA of expression in tumor tissues compared to non- cancerous regions, high expression in non- cancerous regions, increase of mRNA expression in HCT8 cell lines, expression of mRNA in normal tissue |
[317,318,365] | |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Epidermoid carcinoma |
the KB-3-1 epidermoid carcinoma cell line |
immunobl otting, RNase protection assays |
increase of mRNA expression |
[318] | |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Gallbladder carcinoma |
clinical tumor tissue samples, Mz- ChA-1 cells derived from gallbladder adenocarcino ma |
RT-PCR, immunobl otting, immunofl uorescenc e microscop y |
high expression of mRNA |
suggested to contribute to the MDR phenotype, |
[402,403] |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Head and neck carcinoma |
parenteral and cisplatin- resistant head and neck cancer KB cell line |
Northern blotting |
expression of mRNA |
[365] | |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Hepatic carcinoma |
clinical tumor and correspondin g normal tissue samples |
immunobl otting, RT-PCR, immunohi stochemist ry, immunofl uorescenc e microscop y |
increase of mRNA and protein expression, low expression in normal tissue |
suggested to contribute to the intrinsic MDR phenotype |
[323] |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Leukemia | clinical tumor tissue samples, childhoodacu te lymphocytic (lymphoblasti c) leukemia (ALL), bone marrow aspirates or peripheral blood were collected from AML patients |
immunohi stochemist ry, RT- PCR, functional drug efflux, immunobl otting |
expressed of mRNA and protein, expressed in normal tissue, expressed of and protein in PC13, PC13 2-2, HHT90 and HL60/MRP cell lines |
great variability in mRNA expression in AML patient samples, associated with a worse prognosis, suggested to be involved in chemoresistance in AML patients, relapsed patients showed a higher mRNA expression, high expression has an unfavorable prognosis |
[45,322,377,386,410, 411] |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Liver carcinoma |
clinical tumor tissue samples, hepatocellula r carcinoma (HCC) |
RT-PCR, immunohi stochemist ry |
expression of mRNA as in normal tissue |
[396] | |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Lung carcinoma |
non-small cell and small cell lung cancer cell lines not selected for drug resistance, parental lung adenocarcino ma cell line MOR/P, doxorubicin- resistant sublines of the non-small cell lung cancer cell lines SW1573/Sl |
immunobl otting, RNase protection assays, Western immunobl otting, RT-PCR |
increase of mRNA and protein expression, low expression in normal tissue |
suggested as component of the multifactor multidrug resistance phenotype of lung cancer |
[318,319,320] |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Pancreatic carcinoma |
clinical tumor tissue samples, pancreatic cancer cell lines |
reverse- transcripta se (RT)- PCR, RT- PCR, immunohi stochemist ry |
expression of mRNA in some cell lines |
[395] | |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Cancer | Prostate carcinoma |
parental cells and cisplatin- resistant P/CDP5-R cells derived from PC-3 human prostate cancer cells |
Northern blotting |
expression of mRNA in prostate and normal tissue |
[291,365] | |
MRP3,
cMOAT 2, MLP2, MOAT- D, ABCC3 |
Illness | Liver disease |
Primary biliary cirrhosis |
clinical samples, injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplification assay, immunohi stochemist ry |
increase of protein level |
[205] | |
MRP4, MOAT-
B, ABCC4 |
Illness | Cancer | Leukemia | clinical tumor tissue samples, bone marrow aspirates or peripheral blood were collected from AML patients |
RT-PCR | expressed of mRNA, expressed in normal tissue |
great variability in mRNA expression in AML patient samples |
[45,386] |
MRP4, MOAT-
B, ABCC4 |
Illness | Cancer | Lung carcinoma |
non-small cell and small cell lung cancer cell lines not selected for drug resistance |
RT-PCR | low mRNA expression in cell lines, low expression in normal tissue |
no evidence to support involvement in drug resistance |
[318,320] |
MRP4, MOAT-
B, ABCC4 |
Illness | Liver disease |
Acetaminop hen overdoses |
clinical samples, injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplificati on assay, immunohi stochemist ry |
increase of mRNA expression, increase of protein level |
[205] | |
MRP4, MOAT-B,
ABCC4 |
Illness | Liver disease |
Primary biliary cirrhosis |
clinical samples, injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplificati on assay, immunohi stochemist ry |
increase of mRNA expression, increase of protein level |
[205] | |
MRP5,
SMRP, MOAT- C, ABCC5 |
Illness | Cancer | Bladder carcinoma |
the cisplatin- resistant cell lines T24/DDP1O |
RNase protection assays |
low increase of mRNA expression, low expression in normal tissue |
[318] | |
MRP5,
SMRP, MOAT- C, ABCC5 |
Illness | Cancer | Colorectal carcinoma |
the cisplatin- resistant colon carcinoma cell lines HCT8/DDP |
RNase protection assays |
low increase of mRNA expression, low expression in normal tissue |
[318] | |
MRP5,
SMRP, MOAT- C, ABCC5 |
Illness | Cancer | Epidermoid carcinoma |
the cisplatin- resistant cell lines KCP-4 |
RNase protection assays |
low increase of mRNA expression |
[318] | |
MRP5,
SMRP, MOAT- C, ABCC5 |
Illness | Cancer | Leukemia | clinical tumor tissue samples, bone marrow aspirates or peripheral blood were collected from AML patients, leukemia cell lines |
immunohi stochemist ry, RT- PCR, functional drug efflux, immunobl otting |
expressed of mRNA and protein, expressed in normal tissue |
great variability in mRNA expression in AML patient samples, relapsed patients showed a higher mRNA expression, high expression has an unfavorable prognosis |
[45,386,410,411] |
MRP5,
SMRP, MOAT- C, ABCC5 |
Illness | Cancer | Lung carcinoma |
non-small cell and small cell lung cancer cell lines not selected for drug resistance, parental lung adenocarcino ma cell line MOR/P |
immunobl otting, RNase protection assays, RT-PCR |
increase of mRNA expression, low expression in normal tissue |
no evidence to support involvement in drug resistance |
[318,320] |
MRP5,
SMRP, MOAT- C, ABCC5 |
Illness | Cancer | Ovarian carcinoma |
clinical parental ovarian carcinoma cell line 2008 |
immunobl otting, RNase rotection assays |
increase of mRNA expression, low expression in normal tissue |
[318] | |
MRP5,
SMRP, MOAT- C, ABCC5 |
Illness | Liver disease |
Primary biliary cirrhosis |
clinical injured and normal tissue samples |
Western immunobl otting, branched DNA signal amplificati on assay, immunohi stochemist ry |
increase of mRNA expression, increase of protein level |
[205] | |
MRP6,
ARA, MLP1, MOAT- E, ABCC6 |
Illness | Cancer | Leukemia | clinical tumor tissue samples, bone marrow aspirates or peripheral blood were collected from AML patients |
RT-PCR | expression of mRNA, expressed in normal tissue |
relapsed patients showed a higher mRNA expression, high expression has an unfavorable prognosis |
[45] |
NIS,
SLC5A5 |
Illness | Cancer | Gastric carcinoma |
clinical tumor and adjacent tissue samples |
immunobl otting, immunohi stochemist ry |
decrease of expression |
suggested as tumor marker in the diagnosis and prognosis of gastric malignancies |
[89] |
NIS,
SLC5A5 |
Illness | Cancer | Thyroid carcinoma |
clinical tumor tissue samples, thyroid carcinoma tissue samples |
RT-PCR | decrease of mRNA expression |
[144] | |
OATP1A
2, OATP- A, OATP1, OATP, SLC21A 3, SLCO1A 2 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples |
RT-PCR | decrease of mRNA expression in neoplastic colon tissue |
[87] | |
OATP1B
1, OATP- C, OATP2, LST-1, SLC21A 6, SLCO1B 1 |
Illness | Cancer | Colorectal carcinoma |
clinical tumor and normal tissue samples |
RT-PCR | decrease of mRNA expression in neoplastic colon tissue |
[87] | |
OCTN1,
SLC22A 4 |
Illness | Arthritis | Rheumatoid arthritis |
human fibroblast-like synoviocyte cell line MH7A derived from RA patients |
RT-PCR | increase of mRNA expression |
[206] | |
OCTN1,
SLC22A 4 |
Physiologic al condition |
Hypoxia | Decreased oxygen pressure |
BeWo cells, CoCl(2) induced hypoxia |
RT-PCR, Western immunobl otting, Carnitine transport |
increase of mRNA expression, no change of protein level, decreased activity |
[187] | |
PEPT1,
SLC15A 1 |
Physiologic al condition |
Oxidativ e stress |
Reactive oxygen species |
hydrogen peroxide exposure, human colonic epithelial Caco-2 cells |
[14C]glyc ylsarcosin e (Gly- Sar) uptake, Western immunobl otting |
decrease of protein level and activity |
[201] | |
SMIT,
SLC5A3 |
Physiologic al condition |
Cellular osmolalit y |
Hypertonic environmen t |
HaCaT keratinocytes, primary normal human keratinocytes, hyperosmotic exposure |
RT-PCR, osmolyte uptake |
increase of mRNA expression and activity |
[178,212] | |
SMIT,
SLC5A3 |
Physiologic al condition |
Cellular osmolalit y |
Hypotonic environmen t |
primary normal human keratinocytes hyperosmotic exposure |
osmolyte efflux |
increase of activity |
[212] | |
SMIT,
SLC5A3 |
Experiment al condition |
Cellular osmolalit y |
Ultraviolet A and B radiation |
primary normal human keratinocytes, hyperosmotic exposure |
RT-PCR, osmolyte uptake |
increase of mRNA expression and activity |
[212] | |
SMVT,
SLC5A6 |
Food | Dietary habit |
Marginal biotin deficiency |
leukocytes from human blood of normal subjects on egg-white diet, human hepatoma cell line HepG2 |
RT-PCR, Western immunobl otting |
decrease of mRNA and protein expression |
[80,81] | |
SMVT,
SLC5A6 |
Physiologic al condition |
Growth medium concentr ation |
Biotin deficiency |
human- derived renal proximal tubular epithelial HK-2 cells, human intestinal HuTu-80 and Caco-2 cells |
RT-PCR, Western immunobl otting |
increase of mRNA and protein expression |
[82,83] | |
SVCT2,
SLC23A 2 |
Food | Dietary habit |
L-Ascorbic acid depletion |
platelets from healthy donors |
RT-PCR, Western immunobl otting, Vitamin C uptake |
increase of mRNA expression, protein level and activity |
[193] | |
System y(+)L,
SLC7A7 |
Food | Dietary habit |
Amino acid depletion |
platelets from controls and hemodialysis patients |
L-arginine transport |
decrease of activity |
[191] | |
TAUT,
SLC6A6 |
Physiologic al condition |
Cellular osmolalit y |
Hypertonic environmen t |
HaCaT keratinocytes, primary normal human keratinocytes, hyperosmotic exposure |
RT-PCR, osmolyte uptake |
high increase of mRNA expression and activity in HaCaT keratinocyt es |
[178,212] | |
TAUT,
SLC6A6 |
Physiologic al condition |
Cellular osmolalit y |
Hypotonic environmen t |
primary normal human keratinocytes, hyperosmotic exposure |
osmolyte efflux |
increase of activity |
[212] | |
TAUT,
SLC6A6 |
Experiment al condition |
Cellular osmolalit y |
Ultraviolet A and B radiation |
primary normal human keratinocytes hyperosmotic exposure |
RT-PCR, osmolyte uptake |
increase of mRNA expression and activity |
[212] | |
THTR1,
SLC19A 2 |
Illness | Cancer | Breast carcinoma |
breast cancer cell line HS578T |
RT-PCR, Western immunobl otting |
no difference in mRNA, protein expression and activity compared to normal tissues |
[290] | |
THTR1,
SLC19A 2 |
Food | Dietary habit |
Thiamine deficiency |
human- derived renal epithelial HEK-293 c |
RT-PCR, Western immunobl otting |
increase of mRNA expression |
[207] | |
THTR2,
SLC19A 3 |
Illness | Cancer | Breast carcinoma |
breast cancer cell line HS578T |
RT-PCR, Western immunobl otting |
decrease of mRNA, protein expression and activity compared to normal tissues |
down regulation may be associated with the development of increased resistance to apoptosis in these tumors |
[290] |
THTR2,
SLC19A 3 |
Food | Dietary habit |
Marginal biotin deficiency |
leukocytes from human blood of normal subjects on egg-white diet |
RT-PCR, urinary excretion of biotin |
decrease of mRNA and protein expression |
[80] | |
THTR2,
SLC19A 3 |
Food | Dietary habit |
Thiamine deficiency |
human- derived renal epithelial HEK-293 c |
RT-PCR, Western immunobl otting |
increase of mRNA expression |
[207] |
The present summary provides the reader a collection of information on the effects of major disease and environmental factors on function of CYP enzymes and transporters considering also the effects on therapeutic treatment or human health.
Tabular presentation
Data are presented in Tables 1 and 2 and formatted in columns 1 - 9: 1. CYP/Transporter; 2. Category; 3. Subcategory; 4. Effectors; 5. Model used; 6. Method; 7. Effect on particular enzyme or transporter; 8. Remarks about effects when stated by the cited authors to additionally characterize the effects. 9. References. The data are sorted by Column 1 (Enzymes/Transporters), Column 3 (Subcategory), and Column 4 (Effectors) for an easier approach to the information presented. The tabulated data were obtained either in vivo (clinical experiments) or in vitro using various models including clinical tissue samples, cell cultures, microsomes, and recombinant systems. References to the Tables 1 and 2 are listed separately at the end of Table 2 and, in addition, PubMed ID numbers (when available) are included to facilitate the ease of location of cited papers.
It is important to emphasize that in some cases the results depend upon the model and/or method used for investigation and contradictory or insufficient results might have been obtained [7]. Such results are designated in the Tables (bold-face font) as inconsistent results reported. When effects might influence clinical drug effects, they are designated as having clinically significant pharmacokinetic drug-drug interaction potential. Of the effectors presented in Tables 1 and 2, a great number belong to the effects of cancers on the expression/activity of both transporters and CYP enzymes. Particularly intriguing is interpretation of the results such as “increase” or “decrease” of expression of a particular enzyme/transporter. This is because of the lack of exact limits, diversity of ways of presenting results, and the large numbers of results obtained using immunohistochemistry or immunoblotting which are not always expressed quantitatively and thus making the results difficult to compare with those obtained by other methods. Standardized detection and quantification techniques and methods, e.g. real-time PCR (RT-PCR), can provide more reliable comparisons of experimental results with therapy. In this respect it has been suggested that of the techniques used to analyze drug transporters, flow cytometry is preferred to immunoblots, mRNA blots, and immunocytochemical assays. The use of functional flow cytometric tests (assessing modulator-induced changes in fluorophore retention and/or efflux) has been promoted because these allow evaluation of a protein activity, in contrast to immunochemical or molecular tests [8]. E.g. with P-gp functional analysis is preferred when testing effects of cancers as a more sensitive predictor of chemoresistance than P-gp expression [9]. This approach should be considered regarding the effects of inflammation and of environmental factors. Detailed analysis of tumor types and expression of CYP enzymes and transporters has identified a variety of tumors with the same pharmacological profile. It was therefore suggested that the anatomical independence of drug pathways promotes efforts to move away from traditional approaches in the selection of cancer therapy (10).
As presented in Tables 1 and 2 (columns Effects and Remarks) experimental results show that in a number of cases inconsistent results and conclusions have been obtained for the same effectors using different methods and/or models, making it difficult to reach conclusions on the effects of, e.g., tumors and effectors on both CYP and transporter expression and activity. However, some results could link causality with changes of gene expression. For instance, the increases in mRNA and protein expression of glucose transporters (GLUT) were suggested as markers of the aggressive biologic potential of tumors (associated with poor survival of patients). It was suggested that inhibition of up-regulation of these transporters might be a promising tool that would be beneficial in cancer prognosis and therapy. Similarly, increases in expression levels of CYP1B1 and CYP2J2 in tumor cells and tissues (these enzymes otherwise not present or present at very low levels in normal tissues) have been suggested as tumor markers in the diagnosis and prognosis of different malignancies. Although in some cases inconsistent results have been obtained, overexpression and increased functional activity of transporters such as MRPs (in particular MRP1, MRP2, and MRP3), P-gp (MDR1), LRP, and BCRP1 in tumors have been suggested as predictors and to participate in acquired multidrug resistance in vivo. On the other hand, enhanced or lowered expression and/or activity of CYP enzymes in some diseases could result in clinically significant drug interaction potential, resulting in unfavorable clinical outcome or increased drug/chemical toxicity. Some examples include increased expression of CYP2E1 in alcoholic healthy subjects and decreased enzyme expression in alcoholic liver disease (ALD), increased CYP2E1 expression in livers of transplant patients, high expression of CYP3A4 enzyme in lymphoid carcinoma (proposed as a useful predictor of poor response to the standard peripheral type lung cancer (PTLC) chemotherapy), and high expression of CYP3A enzymes in osteosarcomas (suggested as a predictor of metastasis and poor prognosis). For detailed comments related to these and other examples refer to the information in Tables 1 and 2 and the references, and for the levels of the CYP enzymes present in different human tissues the readers should consult the results reported elsewhere [11].
In additions to the effectors reported in Table I and Table II there a number of others that might have additional effects on clinical or toxicological outcome influencing the level or the activity of one or more enzymes or transporters. Such effectors are the genetic polymorphism of CYP enzymes and transporters, as well as the effects of drugs/xenobiotics by themselves. The influence of such effectors are not the focus of the present paper, they were reviewed elsewhere [1,2,12]. For instance, some consistent evidence for association between CYP polymorphisms and lung, head and neck, and liver cancers has been reported. Controversial findings suggest that colorectal and prostate cancers may be associated with CYP polymorphisms, whereas no evidence for relevant associations with breast or bladder cancers has been reported. A summary of the available information related to the association of CYP polymorphisms has been reported [12] with leukemia, lymphomas and diverse types of cancer that were investigated only for some CYP genes, including brain, esophagus, stomach, pancreas, pituitary, cervical epithelium, melanoma, ovarian, kidney, anal, and vulval cancers.
The influence of the drugs themselves can be illustrated by the effect of placitaxel on human colorectal cancer cells (Caco-2). The cells (which are sensititive) were exposed to increasing concentrations of the drug (0-250 nM) during the course of one year, in order to select placitaxel-resistant cells. Subsequently, the sensitivity to placitaxel and the extents of expression of CYP2C8, CYP3A4, and CYP3A5 genes in the original and resistant cells were compared. The results showed that resistant cancer cells displayed a 246-fold increased lethal dose (LD50) to placitaxel compared with the original cancer cells. In addition, a 4.4-fold enhancement of CYP2C8 expression and a 5.6-fold increase of multidrug resistance (MDR)1 expression was observed in resistant cells exposed to placitaxel. When placitaxel was removed from the culture medium, CYP2C8 (but not MDR1) expression, reverted to basal levels and the resistance to placitaxel decreased 3.2-fold. No major changes in the expression levels of CYP3A4 and CYP3A5 were observed. It was concluded that Caco-2 cells are capable of increasing the expression levels of CYP2C8 as a response to long-term exposure to placitaxel. This study provides evidence for a mechanism of acquired resistance to anticancer therapy based on the induction of anticancer-metabolizing enzymes [13]. It is noteworthy to mention that placitaxel has been reported as a selective substrate of CYP2C8 and also CYP3A4, and both enzymes are present in non-tumoral and tumoral tissue samples (thus inactivating the drug). In addition, the enzyme activities when induced or inhibited either in GI tract or in liver might have clinically significant effects on pharmacokinetic properties of the drug (Table 1) (2,13,14).
Acknowledgement
This work is dedicated to the family of the corresponding author (R.S.), including wife Vjekoslava, son Borut, and daughter Petra.
Footnotes
Declaration of interest: The authors report no financial conflicts of interest.
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