Table 3.

Tissue distribution of 5α-reductase 1–3 according to different authors.

Author isozymes studied	Tissue type	Materials and methods	5α-R1	5α-R2	Notes
Eicheler et al. [10] 5α-R1-2	Epidermis: genital (scrotum) nongenital (Axilla, breast, lip, eyelid) using a semiquantitative visual scale	Protein expression (IHC) using rabbit polyclonal antibodies against synthetic peptides from C-terminus parts of 5α-R1-2 proteins. Antibody sensitivity and specificity confirmed by ELISA and WB on FFPE biopsy or autopsy tissues	Nuclear, in epidermis from all sites: (scrotal> axilla> breast> lip> eye lid): stratum basale (++), stratum spinosum (++), absent in stratum granulosum and stratum corneum, dermal papillae, fibrous and outer epithelial RS (++), inner epithelial RS (+), matrix cells of hair bulb (++), scrotal fibroblast (++), basal and secretory cells of sebaceous glands (++), secretory and myoepithelial cells of sweat glands (++), arrector pili muscles (+), dermal adipocytes (+). No qualitative differences in males and females	Cytoplasmic, in epidermis from all sites: stratum spinosum (++), stratum basale (+), absent in stratum granulosum and stratum corneum, inner epithelial RS (++), matrix cells of hair bulb (+), absent in dermal papillae, fibrous and outer epithelial RS, basal (+) and glandular (−) cells of sebaceous glands, myoepithelial (+) and secretory cells (−) of sweat glands, dermal adipocytes (+) No qualitative differences in males and females	5α-R1 more uniformly spread in skin versus 5α-R2 that is mainly found in inner epith RS
Aumüller et al. [11] 5α-R1-2	Many tissue types, using a semiquantitative visual scale	Protein expression (IHC) using rabbit polyclonal antibodies against synthetic peptides from C-terminus parts of 5α-R1-2 proteins. Antibody sensitivity and specificity confirmed by ELISA and WB. Tissues from surgical pts and autopsies, fixed in Bouin's or formaldehyde	Mainly nuclear: Prostate: stroma (+), epithelium (+) Seminal vesicle: stroma (+), epithelium (+) Epididymis: stroma (+), epithelium (+) Testis: Leydig cells (+), Sertoli cells (+) Ovary: stroma (++), theca and granulosa cells (−) Uterus: endometrium (+), myometrium (+) Liver: hepatocytes (+/−), bile duct c (+), kupffer cells (++) Pancreas: exocrine (+), islets of Langerhans (−) Kidney: glomerulus (+), PT (−), DT (++), CD (+) Adrenal: cortex (−), medulla (−) Thyroid: thyrocytes (−), C cells (−) Cerebral cortex: pyramidal c (+), glial cells (+/−) Pituitary: prolactin cells (+), others (−)	Mainly cytoplasmic: Prostate: stroma (+), epithelium (++), specially basal cells Seminal vesicle.: stroma (+), epithelium (++) Epididymis: stroma (+), epithelium (+) Testis: spermatogonia (+), Leydig and Sertoli cell (−) Ovary: stroma (+), theca and granulosa cells (+/−) Uterus: endometrium (+), myometrium (+) Liver: hepatocytes (++), bile duct c (+), kupffer cells (−) Pancreas: exocrine (+), islets of Langerhans (−) Kidney: glomerulus (−), PT (++), DT (+/−), CD (+) Adrenal: ZG (+), ZF (+/−), ZR (+/−), med (−) Thyroid: thyrocytes (−), C cells (−) Cerebral cortex: pyramidal c (++), glial c (−) Pituitary: prolactin cells (+), others (−)	5α1-2 is ubiquitous
Bayne et al. [12] 5α-R1-2	Scalp biopsies from bald and non-bald men	Protein expression (IHC) using validated mouse monoclonal antibodies against peptides from N-terminus parts of 5α-R1-2 and enzyme activity using 3H-T	In balding and non-balding scalp: 5α-R1 is expressed only in sebaceous glands No expression was detected in hair follicles or in epidermis	In balding and nonbalding scalp: 5α-R2 is expressed in infundibula, outer (mainly) and inner epithelial RS of hair follicles. No expression was detected in dermal papillae or in sebaceous glands
Thigpen et al. [13] 5α-R1-2	Autopsy and surgical tissue samples	Messenger RNA (NB) and protein expression (IHC and WB) using rabbit polyclonal antibodies against peptides from C-terminus parts of 5α-R1-2	5α-R1 protein is expressed in liver and chest skin and 5α-R1 mRNA was detected in cerebellum, hypothalamus, pons, medulla oblongata, skin, and liver 5α-R1 was not detected by WB in any fetal tissue. 5α-R1 was detected by WB in newborn liver, skin, and scalp.5α-R1 was detected by WB in all scalp samples from balding and nonbalding men (except one). It was not detected in any normal prostate, BPH, or PC sample	5α-R2 protein is expressed in prostate, seminal vesicles, epididymis, and liver. 5α-R2 mRNA was detected in prostate, SV, epididymis. and liver. 5α-R2 was detected by WB only in fetal genital skin (not detected in fetal liver, adrenal, testis, ovary, scalp, and brain). 5α-R2 was detected by WB in newborn prostate, SV, epididymis, liver, skin. and scalp. 5α-R2 was not detected by WB in any sample of balding and nonbalding scalp from one man. It was detected in all normal prostate, BPH, and PC samples	5α-R1 protein was not detected in any prostate sample
Thomas et al. [14] 5α-R1-2	Prostate: BPH (TURP), ASCaP (RP), CaP metastasis in androgen deprivation-treated men (autopsy)	Protein expression (IHC) using rabbit polyclonal antibodies against peptides from N-terminus of 5α-R1-2 proteins. Antibody specificity confirmed with WB on naïve, 5α-R1- and 5α-R2- transfected COS-1 cells and IHC on transfected COS-1 cells-Evaluated by measuring percentage of moderate- and high-intensity immunostaining areas in relation to total epithelial, PIN, or tumor area in PE tissues	Nuclear in BPH, shifts to cytoplasm in HGPIN and CaP Immunostaining intensity: Metastasis> CR-CaP> AS-CaP = HGPIN> BPH	Mainly cytoplasmic in all specimens Immunostaining intensity: BPH = Metastasis = CR-CaP> AS-CaP = HGPIN	All differences are statistically significant
Thomas et al. [14] 5α-R1-2	Prostate: AS-CaP (RP) with Gleason score <7, 7, >7	Protein expression (IHC) using validated rabbit polyclonal antibodies, evaluated by visually estimating percent of total tumor area showing low-, moderate, and high-intensity in relation to Gleason score	Mainly nuclear in BPH, nuclear and cytoplasmic in CaP (all grades), and in adjacent benign epithelial tissue Immunostaining intensity: High grade > moderate grade = low grade > PC-adjacent benign tissue > BPH	Mainly cytoplasmic in all samples (benign and malignant) Immunostaining intensity: BPH> high grade> moderate grade = low grade = adjacent benign tissue	Staining in CaP-adjacent benign tissue is not significanty different from low- and high-grade CaP for either isozyme
Söderstöm et al. [15] 5α-R1-2	Prostate: BPH (TURP) and AS-CaP via RP or RC	Messenger RNA expression (sqRT-PCR) and measurement of 5α-R enzyme activity at pH 5.5 and 7 using 14C-T at 37°C in homogenized frozen pulverized prostate tissue	5α-R1 mRNA expression is similar in BPH and AS-CaP. There was no correlation between enzyme activity at pH (5.5 and 7) and 5α-R1 mRNA expression as expressed on the basis of β-actin	5α-R2 mRNA and enzyme activity were higher in BPH than in AS-CaP. There was a positive correlation between enzyme activity at pH 5.5 and expression of 5α-R2 mRNA as expressed on the basis of β-actin
Lehle et al. [61] 5α-R 1-2	BPH and CaP tissue post prostate biopsy or RP frozen in liquid nitrogen, one human liver sample	Messenger RNA expression (ISH, sqRT-PCR)	ISH showed that 5α-R1 mRNA is expressed in epithelium > stroma mRNA expression levels by sqRT-PCR: liver> CaP > BPH> Normal prostate	ISH showed that 5α-R2 mRNA is expressed in epithelium > stroma mRNA expression levels by sqRT-PCR: liver = BPH > Normal prostate > CaP
Habib et al. [16] 5α-R1-2	BPH tissue (TURP) frozen in liquid nitrogen or in ice-cold RPMI with FBS and archival PE-BPH tissue	Messenger RNA expression (ISH, RT-PCR) and measurement of enzyme activity at pH 5 and 7.5 using 3H-T at 37°C in homogenized pulverized frozen prostate tissue	5α-R1 mRNA expressed in epithelium > stroma	5α-R1 mRNA expressed in epithelium > stroma 5α-R2 mRNA > 5α-R1 mRNA in BPH 5α-R2 enzyme activity ≫ 5α-R1 enzyme activity in homogenized BPH tissue
Bonkhoff et al. [17] 5α-R1-2	BPH (TURP), AS-CaP (RP), CR-CaP (channeling TUR)	Protein expression (IHC) using polyclonal rabbit antibodies against peptides from C-terminus parts of 5α-R1 and 2, validated by ELISA and WB	Mainly nuclear, in normal prostate and BPH tissue (luminal epithelial > basal) and in stroma 5α-R1 immunostaining > 5α-R2 in BPH (in both epithelium and stroma). In CaP, 5α-R1 immunostaining became nuclear and cytoplasmic and more intense in HGPIN and CaP versus adjacent benign tissue (specially CR-CaP)	Mainly cytoplasmic (weak), in normal prostate and BPH tissue (basal > luminal epithelial) and stroma. In CaP, 5α-R2 immunostaining became nuclear and cytoplasmic and more intense in HGPIN and CaP versus adjacent benign tissue (specially CR-CaP)
Shirakawa et al. [18] 5α-R1-2	BPH (RC) fixed in formaldehyde and paraffin-embedded	Messenger RNA (qRT-PCR), protein (IHC) expression using polyclonal rabbit antibodies against peptides from C-terminus parts of 5α-R1 and 2, validated by ELISA and enzyme activities at pH 5 and 7.5 using 3H-T at 37°C	5α-R1 mRNA copy numbers> 5α-R2 mRNA in BPH 5α-R1 protein expression is intense in epithelium of BPH (higher than 5α-R2 protein) 5α-R1 enzyme activity at pH 7.5 is similar to 5α-R2 enzyme activity at pH 5.0	5α-R2 mRNA < 5α-R1 mRNA in BPH 5α-R2 protein expression is detected in epithelium and stroma of BPH (less intense than 5α-R1)
Titus et al. [19] 5α-R1-2	ASBP, AS-CaP and CR-CaP (RP or channeling TURP) tissue that was FFPE or snap frozen in liquid nitrogen	Protein expression (by IHC in TMAs that are quantified by visual scoring and digital image analysis and by WB) and enzyme activity in homogenized pulverized prostate tissue using 3H-ASD at 37°C	5α-R1 is nuclear and cytoplasmic in all 3 tissues Nuclear 5α-R1 staining intensity: ASBP = AS-CaP = CR-CaP Cytoplasmic 5α-R1 staining intensity: ASBP = AS-CaP> CR-CaP Not detected in stroma in any of the 3 tissues In WB, 5α-R1 > 5α-R2 in all 3 tissues 5α-R1 enzyme activity > 5α-R2 in CR-CaP (3 folds)	5α-R2 is mainly cytoplasmic in all 3 tissues Nuclear 5α-R2 staining intensity: ASBP = AS-CaP> CR-CaP Cytoplasmic 5α-R2 staining intensity: ASBP = AS-CaP> CR-CaP Not detected in stroma in any of the 3 tissues In WB, 5α-R2 was undetectable in CR-CaP 5α-R2 activity > 5α-R1 in ASBP and AS-CaP	In all 3 tissues, expression of 5α-R1 is consistenty more than 5α-R2 (in nucleus) but similar in cytoplasm
Godoy et al. [20] 5α-R3	Benign and malignant human tissue TMAs	Protein expression (IHC) using validated monoclonal mouse antibody against peptide from N-terminus of 5α-R3 protein and quantified by visual scoring and digital image analysis	5α-R3 was mainly cytoplasmic Benign tissue immunostaining: Kidney (PT,DT ++), liver (++), exocrine pancreas (++), skeletal muscle (+), skin (strata basale and spinosum ++), gastric epithelial cells (+), myometrium (++) Malignant tissue: colon adenoCA (++), esophageal adenoCA (++), RCC (++), HCC (++), ovarian mucinous CA (++), stomach adenoCA (++), testis seminoma and YS tumor (++), thyroid papillary CA (++), endometrioid CA (++), breast CA (+) ASBP: basal epithelial cells, HGPIN: benign basal and neoplastic epithelial cells, AS-CaP and CR-CaP: in neoplastic cells (5α-R3 immunostaining intensity: AS-CaP = CR-CaP > ASBP)		5α-R3 protein expression ↑ in the cytoplasm of malignant cells versus benign cells in prostate, testis, thyroid, lung and breast CA
Yamana et al. [21] 5α-R3	20 benign human tissues, CaP, and breast cancer cell lines	5α-R1-3 mRNA expression (RT-PCR) and measurement of 5α-R 1–3 enzyme activity using 14C-labelled ASD and T in intact cells in culture	5α-R3 expression at the mRNA level is higher than 5α-R1 and 2 in frontal cortex, heart, colon, stomach, liver, pancreas, lung, BPH, prostate, testis, mammary gland, brain, cervix, ovary, dermis, epidermis, total skin, small intestine, spleen, and kidney 5α-R2 mRNA was the most abundant in BPH and muscle Finasteride inhibits 5α-R2 and 5α-R3 with similar potency (IC50 = 14.3 nM, 17.4 nM, resp.). Dutasteride is a more potent inhibitor of 5α-R3 than finasteride (IC50 = 0.33 nM)		5α-R3 is ubiquitous Dutasteride is a triple 5α-RI in vitro

ELISA: enzyme-linked immunosorbant assay; IHC: immunohistochemistry; WB: western blot; NB: northern blot; FFPE: formalin fixed paraffin embedded; RS: root sheath; RP: radical prostatectomy; sqRT-PCR: semiquantitative reverse transcriptase-polymerase chain reaction; PE: paraffin-embedded; RPMI: Roswell Park Memorial Institute; FBS: fetal bovine serum; PT: proximal tubules; DT: distal tubules; CD: collecting ducts; TURP: transurethral resection of prostate; RC: radical cystectomy; HGPIN: high-grade prostate intraepithelial neoplasia; ISH: in situ hybridization; RCC: renal cell carcinoma; HCC: hepatocellular carcinoma; adenoCA: adenocarcinoma; CA: carcinoma; YS: yolk sac; TMA: tissue microarray.