Pretranslational up-regulation of the hepatic microsomal δ 4-3-oxosteroid 5α-oxidoreductase in male rat liver by all- trans-retinoic acid

Abstract

Administration of all- trans-retinoic acid (ATRA; 60 mg/kg daily for 3 days) to male rats increased the rate of 5α-dihydrotestosterone (5α-DHT) formation from testosterone in microsomal fractions in vitro. The formation of androstane-3α,17β-diol from testosterone was also increased because of the higher concentration of 5α-DHT produced in microsomal incubations. Northern analysis confirmed that the increased rate of 5α-DHT formation was due to the pretranslational up-regulation in Δ 4-3-oxosteroid 5α-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 5α-reductase activity to that observed in untreated male rat liver. Although these treatments did not decrease 5α-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 16α-hydroxylation activity) was correspondingly decreased by treatments that increased steroid 5α-reductase activity. Thus, gonadectomy in combination with ATRA administration effected a more pronounced decrease in 16α-hydroxylation activity than either treatment alone. These findings suggest that ATRA is a novel positive regulator of the 5α-reductase that in combination with the removal of circulating androgen, which normally suppresses 5α-reductase levels, feminizes the expression of this enzyme in rat liver.