CYP1B1 expression is higher in the peripheral zone compared to the transition zone : a difference underlying zonal susceptibility to prostate adenocarcinoma?

Abstract

Introduction The prostate is a composite organ divided into zones. Prostate adenocarcinoma (CaP) mostly occurs in the peripheral zone. Cytochrome P-450 (CYP) isoenzymes are constitutively expressed and inducible enzymes, many of which (e.g. CYP1A1, CYP1A2 and CYP1B1 isoforms) are involved in hormone and carcinogen hydroxylation. Aim To assess variations in CYP expression in the prostate on an intra-(peripheral zone Vs. transition zone) and inter-individual basis. Materials and Methods Human prostates (n=24) were obtained, with ethical approval, from radical retropubic prostatectomies. Study participants exhibited low PSA (< 20 \ensuremathμg/l serum) and low volume of disease (< two/eight core biopsies positive for CaP). Following resection, tissue sets consisting of peripheral zone and transition zone were isolated from a lobe pre-operatively identified as negative for CaP. A histopathologist always examined adjacent tissue. Real-time RT-PCR was employed to quantitatively examine CYP1A1, CYP1A2 and CYP1B1. Results CYP1A1 mRNA transcripts were detected in either or both zones of twenty tissue sets (in seven cases, in both zones) and were undetectable in four others. In eleven tissue sets, higher levels of CYP1A1 expression were observed in the peripheral zone compared to the transition zone (maximum six-fold difference) whereas in nine other tissue sets this relationship (maximum 2.5- fold difference) was reversed. CYP1A2, although detectable in twelve tissue sets, was not quantifiably expressed. CYP1B1 expression was detected in both zones of all tissue sets examined. Inter-individual variation in CYP1B1 expression levels in peripheral zone (five-fold differences) and transition zone (tenfold differences) were noted. In sixteen out of seventeen tissue sets found to be cancer free, CYP1B1 expression was found to be two- to fifty-fold higher in the peripheral zone compared to the transition zone; in the remaining tissue set an equal level of gene expression was detected in both zones. In the tissue sets containing CaP, CYP1B1 expression was higher in the cancerous zone (be it peripheral or transition) in five of six cases; in another tissue set containing PIN, an equal level of gene expression was again detected in both zones. Immunohistochemistry clearly demonstrated a nuclear staining pattern for CYP1B1 in epithelial and stromal cells of both zones; the staining density of this protein was markedly elevated in cancerous tissue. Discussion CYP1B1 preferentially catalyses the 4-hydroxylation of 17\ensuremathβ- oestradiol, metabolically activates exogenous pro-carcinogens and inactivates anticancer agents. Future studies will investigate whether CYP1B1 may be employed as a target either for chemoprevention strategies or treatment of clinically invasive disease.