Pretranslational up-regulation of the hepatic microsomal delta4-3-oxosteroid 5alpha-oxidoreductase in male rat liver by all-trans-retinoic acid.
Administration of all-trans-retinoic acid (ATRA; 60 mg/kg daily for 3 days) to male rats increased the rate of 5alpha-dihydrotestosterone (5alpha-DHT) formation from testosterone in microsomal fractions in vitro. The formation of androstane-3alpha,17beta-diol from testosterone was also increased because of the higher concentration of 5alpha-DHT produced in microsomal incubations. Northern analysis confirmed that the increased rate of 5alpha-DHT formation was due to the pretranslational up-regulation in delta4-3-oxosteroid 5alpha-oxidoreductase (EC 1.3.99.5) mRNA expression in ATRA-treated male rat liver. Thus, ATRA elicited in male rat liver a partial feminization of the expression of this enzyme, which normally exhibits a female-selective distribution in the rat. Subsequent experiments evaluated whether the administration of human chorionic gonadotropin or thyroxine to ATRA-treated male rats decreases 5alpha-reductase activity to that observed in untreated male rat liver. Although these treatments did not decrease 5alpha-reductase to untreated male levels, it was found that administration of ATRA to gonadectomized male rats produced complete feminization of the enzyme. Again, up-regulation was confirmed at the mRNA level. The activity of the male-specific cytochrome P450 2C11 (as reflected by microsomal testosterone 16alpha-hydroxylation activity) was correspondingly decreased by treatments that increased steroid 5alpha-reductase activity. Thus, gonadectomy in combination with ATRA administration effected a more pronounced decrease in 16alpha-hydroxylation activity than either treatment alone. These findings suggest that ATRA is a novel positive regulator of the 5alpha-reductase that in combination with the removal of circulating androgen, which normally suppresses 5alpha-reductase levels, feminizes the expression of this enzyme in rat liver.
Murray
M
M
School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia. M.Murray@unsw.edu.au
Butler
A M
AM
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D001711:Biotransformation; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D000072467:Cytochrome P450 Family 2; D013196:Dihydrotestosterone / Q000378:metabolism; D004790:Enzyme Induction; D006728:Hormones / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase; D013739:Testosterone / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D006728:Hormones; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D013739:Testosterone; D009249:NADP; D014212:Tretinoin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase