Abstract
Renal cell cancer is the main malignant tumour of the kidney and has an increasing incidence. This type of tumour has a poor prognosis and shows intrinsic resistance to several anti-cancer drugs. The CYP3A P450 family, which consists of three closely related forms, is involved in the oxidative activation and deactivation of a variety of carcinogens and several anti-cancer drugs. In this study the presence and cellular localization of CYP3A has been investigated using a combination of immunohistochemistry, immunoblotting and reverse transcriptase polymerase chain reaction (RT-PCR) in renal cell cancer and corresponding normal kidney. CYP3A was consistently expressed in both renal call cancer and in normal kidney. In renal cell cancer, CYP3A was localized to tumour cells and in normal kidney the predominant cellular localization of CYP3A was to proximal tubular epithelial cells. RT-PCR showed that both CYP3A5 mRNA and CYP3A7 mRNA were consistently present in both tumour and normal samples, while CYP3A4 mRNA was present in 65% of tumours and 90% of normal samples. This study indicates that individual members of the CYP3A family are expressed in renal cell cancer. The presence of CYP3A in renal cell cancer might be important in the metabolic potentiation as well as the detoxification of chemotherapeutic agents used to renal cancer. © 1999 Cancer Research Campaign
Keywords: cytochrome P450, kidney, neoplasm
Full Text
The Full Text of this article is available as a PDF (496.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anttila S., Hukkanen J., Hakkola J., Stjernvall T., Beaune P., Edwards R. J., Boobis A. R., Pelkonen O., Raunio H. Expression and localization of CYP3A4 and CYP3A5 in human lung. Am J Respir Cell Mol Biol. 1997 Mar;16(3):242–249. doi: 10.1165/ajrcmb.16.3.9070608. [DOI] [PubMed] [Google Scholar]
- Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
- Capdevila J. H., Falck J. R., Estabrook R. W. Cytochrome P450 and the arachidonate cascade. FASEB J. 1992 Jan 6;6(2):731–736. doi: 10.1096/fasebj.6.2.1537463. [DOI] [PubMed] [Google Scholar]
- Chang T. K., Weber G. F., Crespi C. L., Waxman D. J. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res. 1993 Dec 1;53(23):5629–5637. [PubMed] [Google Scholar]
- Chapman A. E., Goldstein L. J. Multiple drug resistance: biologic basis and clinical significance in renal-cell carcinoma. Semin Oncol. 1995 Feb;22(1):17–28. [PubMed] [Google Scholar]
- Fritz P., Behrle E., Beaune P., Eichelbaum M., Kroemer H. K. Differential expression of drug metabolizing enzymes in primary and secondary liver neoplasm: immunohistochemical characterization of cytochrome P4503A and glutathione-S-transferase. Histochemistry. 1993 Jun;99(6):443–451. doi: 10.1007/BF00274096. [DOI] [PubMed] [Google Scholar]
- Gonzalez F. J., Gelboin H. V. Role of human cytochromes P450 in the metabolic activation of chemical carcinogens and toxins. Drug Metab Rev. 1994;26(1-2):165–183. doi: 10.3109/03602539409029789. [DOI] [PubMed] [Google Scholar]
- Guengerich F. P. Metabolic activation of carcinogens. Pharmacol Ther. 1992;54(1):17–61. doi: 10.1016/0163-7258(92)90050-a. [DOI] [PubMed] [Google Scholar]
- Haehner B. D., Gorski J. C., Vandenbranden M., Wrighton S. A., Janardan S. K., Watkins P. B., Hall S. D. Bimodal distribution of renal cytochrome P450 3A activity in humans. Mol Pharmacol. 1996 Jul;50(1):52–59. [PubMed] [Google Scholar]
- Harris J. W., Rahman A., Kim B. R., Guengerich F. P., Collins J. M. Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme. Cancer Res. 1994 Aug 1;54(15):4026–4035. [PubMed] [Google Scholar]
- Janardan S. K., Lown K. S., Schmiedlin-Ren P., Thummel K. E., Watkins P. B. Selective expression of CYP3A5 and not CYP3A4 in human blood. Pharmacogenetics. 1996 Oct;6(5):379–385. doi: 10.1097/00008571-199610000-00001. [DOI] [PubMed] [Google Scholar]
- Kawajiri K., Fujii-Kuriyama Y. P450 and human cancer. Jpn J Cancer Res. 1991 Dec;82(12):1325–1335. doi: 10.1111/j.1349-7006.1991.tb01800.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kitada M., Kamataki T. Cytochrome P450 in human fetal liver: significance and fetal-specific expression. Drug Metab Rev. 1994;26(1-2):305–323. doi: 10.3109/03602539409029800. [DOI] [PubMed] [Google Scholar]
- Kivistö K. T., Fritz P., Linder A., Friedel G., Beaune P., Kroemer H. K. Immunohistochemical localization of cytochrome P450 3A in human pulmonary carcinomas and normal bronchial tissue. Histochem Cell Biol. 1995 Jan;103(1):25–29. doi: 10.1007/BF01464472. [DOI] [PubMed] [Google Scholar]
- Kivistö K. T., Griese E. U., Fritz P., Linder A., Hakkola J., Raunio H., Beaune P., Kroemer H. K. Expression of cytochrome P 450 3A enzymes in human lung: a combined RT-PCR and immunohistochemical analysis of normal tissue and lung tumours. Naunyn Schmiedebergs Arch Pharmacol. 1996 Jan;353(2):207–212. doi: 10.1007/BF00168759. [DOI] [PubMed] [Google Scholar]
- Kivistö K. T., Kroemer H. K., Eichelbaum M. The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions. Br J Clin Pharmacol. 1995 Dec;40(6):523–530. doi: 10.1111/j.1365-2125.1995.tb05796.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kovacs G., Akhtar M., Beckwith B. J., Bugert P., Cooper C. S., Delahunt B., Eble J. N., Fleming S., Ljungberg B., Medeiros L. J. The Heidelberg classification of renal cell tumours. J Pathol. 1997 Oct;183(2):131–133. doi: 10.1002/(SICI)1096-9896(199710)183:2<131::AID-PATH931>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
- Massaad L., de Waziers I., Ribrag V., Janot F., Beaune P. H., Morizet J., Gouyette A., Chabot G. G. Comparison of mouse and human colon tumors with regard to phase I and phase II drug-metabolizing enzyme systems. Cancer Res. 1992 Dec 1;52(23):6567–6575. [PubMed] [Google Scholar]
- McFayden M. C., Melvin W. T., Murray G. I. Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. Biochem Pharmacol. 1998 Mar 15;55(6):825–830. doi: 10.1016/s0006-2952(97)00516-9. [DOI] [PubMed] [Google Scholar]
- McKay J. A., Weaver R. J., Murray G. I., Ewen S. W., Melvin W. T., Burke M. D. Localization of microsomal epoxide hydrolase in normal and neoplastic human kidney. J Histochem Cytochem. 1995 Jun;43(6):615–620. doi: 10.1177/43.6.7769232. [DOI] [PubMed] [Google Scholar]
- McKinnon R. A., Burgess W. M., Hall P. M., Roberts-Thomson S. J., Gonzalez F. J., McManus M. E. Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues. Gut. 1995 Feb;36(2):259–267. doi: 10.1136/gut.36.2.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Motzer R. J., Bander N. H., Nanus D. M. Renal-cell carcinoma. N Engl J Med. 1996 Sep 19;335(12):865–875. doi: 10.1056/NEJM199609193351207. [DOI] [PubMed] [Google Scholar]
- Murray G. I., Barnes T. S., Sewell H. F., Ewen S. W., Melvin W. T., Burke M. D. The immunocytochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol. 1988 Apr;25(4):465–475. doi: 10.1111/j.1365-2125.1988.tb03331.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray G. I., Barnes T. S., Sewell H. F., Ewen S. W., Melvin W. T., Shaw P. M., Fowler J., Burke M. D. Cytochrome P-450 localization in normal human adult and foetal liver by immunocytochemistry using a monoclonal antibody against human cytochrome P-450. Histochem J. 1987 Oct-Nov;19(10-11):537–545. doi: 10.1007/BF01687361. [DOI] [PubMed] [Google Scholar]
- Murray G. I., Pritchard S., Melvin W. T., Burke M. D. Cytochrome P450 CYP3A5 in the human anterior pituitary gland. FEBS Lett. 1995 May 1;364(1):79–82. doi: 10.1016/0014-5793(95)00367-i. [DOI] [PubMed] [Google Scholar]
- Murray G. I., Taylor M. C., Burke M. D., Melvin W. T. Enhanced expression of cytochrome P450 in stomach cancer. Br J Cancer. 1998 Apr;77(7):1040–1044. doi: 10.1038/bjc.1998.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray G. I., Taylor M. C., McFadyen M. C., McKay J. A., Greenlee W. F., Burke M. D., Melvin W. T. Tumor-specific expression of cytochrome P450 CYP1B1. Cancer Res. 1997 Jul 15;57(14):3026–3031. [PubMed] [Google Scholar]
- Murray G. I., Weaver R. J., Paterson P. J., Ewen S. W., Melvin W. T., Burke M. D. Expression of xenobiotic metabolizing enzymes in breast cancer. J Pathol. 1993 Mar;169(3):347–353. doi: 10.1002/path.1711690312. [DOI] [PubMed] [Google Scholar]
- Nebert D. W. Drug-metabolizing enzymes in ligand-modulated transcription. Biochem Pharmacol. 1994 Jan 13;47(1):25–37. doi: 10.1016/0006-2952(94)90434-0. [DOI] [PubMed] [Google Scholar]
- Nelson D. R., Koymans L., Kamataki T., Stegeman J. J., Feyereisen R., Waxman D. J., Waterman M. R., Gotoh O., Coon M. J., Estabrook R. W. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 1996 Feb;6(1):1–42. doi: 10.1097/00008571-199602000-00002. [DOI] [PubMed] [Google Scholar]
- Patterson L. H. Rationale for the use of aliphatic N-oxides of cytotoxic anthraquinones as prodrug DNA binding agents: a new class of bioreductive agent. Cancer Metastasis Rev. 1993 Jun;12(2):119–134. doi: 10.1007/BF00689805. [DOI] [PubMed] [Google Scholar]
- Roberts-Thomson S. J., McManus M. E., Tukey R. H., Gonzalez F. J., Holder G. M. Metabolism of polycyclic aza-aromatic carcinogens catalyzed by four expressed human cytochromes P450. Cancer Res. 1995 Mar 1;55(5):1052–1059. [PubMed] [Google Scholar]
- Sarabia S. F., Zhu B. T., Kurosawa T., Tohma M., Liehr J. G. Mechanism of cytochrome P450-catalyzed aromatic hydroxylation of estrogens. Chem Res Toxicol. 1997 Jul;10(7):767–771. doi: 10.1021/tx970021f. [DOI] [PubMed] [Google Scholar]
- Schuetz E. G., Schuetz J. D., Grogan W. M., Naray-Fejes-Toth A., Fejes-Toth G., Raucy J., Guzelian P., Gionela K., Watlington C. O. Expression of cytochrome P450 3A in amphibian, rat, and human kidney. Arch Biochem Biophys. 1992 Apr;294(1):206–214. doi: 10.1016/0003-9861(92)90159-t. [DOI] [PubMed] [Google Scholar]
- Schuetz J. D., Beach D. L., Guzelian P. S. Selective expression of cytochrome P450 CYP3A mRNAs in embryonic and adult human liver. Pharmacogenetics. 1994 Feb;4(1):11–20. doi: 10.1097/00008571-199402000-00002. [DOI] [PubMed] [Google Scholar]
- Shaw P. M., Barnes T. S., Cameron D., Engeset J., Melvin W. T., Omar G., Petrie J. C., Rush W. R., Snyder C. P., Whiting P. H. Purification and characterization of an anticonvulsant-induced human cytochrome P-450 catalysing cyclosporin metabolism. Biochem J. 1989 Nov 1;263(3):653–663. doi: 10.1042/bj2630653. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stadler W., Vogelzang N. J. Human renal cancer carcinogenesis: a review of recent advances. Ann Oncol. 1993 Jun;4(6):451–462. doi: 10.1093/oxfordjournals.annonc.a058550. [DOI] [PubMed] [Google Scholar]
- Walker D., Flinois J. P., Monkman S. C., Beloc C., Boddy A. V., Cholerton S., Daly A. K., Lind M. J., Pearson A. D., Beaune P. H. Identification of the major human hepatic cytochrome P450 involved in activation and N-dechloroethylation of ifosfamide. Biochem Pharmacol. 1994 Mar 29;47(7):1157–1163. doi: 10.1016/0006-2952(94)90387-5. [DOI] [PubMed] [Google Scholar]
- Yagoda A., Abi-Rached B., Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol. 1995 Feb;22(1):42–60. [PubMed] [Google Scholar]