Testosteroneの代謝に及ぼすAnti-androgenの影響 (第II報):肝Testosterone 5α-, 5β-Reductaseに及ぼす各種薬物の効果とその調節因子について

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The administration of chlormadinone acetate or estradiol benzoate to male rats causes a significant fall in plasma testosterone levels and an increase in the activity of hepatic testosterone A ring reduction. The metabolism of testosterone-4--14C was studied in the microsomal fraction, and 105,000 × g supernatant fraction of the livers of normal male and hypophysectomized male rats that had been treated with chlormadinone acetate, estradiol benzoate, phenobarbital, or 3-methylcholanthrene. 100 mg/kg of chlormadinone acetate or 1 mg/kg of estradiol benzoate was administrated to separate groups of male rats daily for 5 weeks and 9 days, respectively. The conversion of testosterone to 5α-dihydrotestosterone in the hepatic microsome was increased approximately 2-3 times by the treatment of chlormadinone acetate or estradiol benzoate. However, the 5β-reductase in 105,000 × g supernatant was little influenced by chlormadinone acetate and estradiol benzoate. When estradiol benzoate was administered to hypophysectomized male rats, 5α-reductase activity was not induced. These findings indicate an essential role of the pituitary gland in the regulation of _??_4-5α-reductase. On the other hand, when phenobarbital or 3-methylcholanthrene, inducer of the drug oxidizing enzymes in the liver, was administered to normal and hypophysectomized rats, there was a substantial depression of 5α-reductase activity without any effects on 5β-reductase. However, the microsome caused a 50% increase in aniline hydroxylation activity. The results showed that phenobarbital not only enhanced the oxidative drug metabolism in the liver as expected but also decreased hepatic _??_4-5α-reductase activity to increase the ratio of 5β/5α-metabolites formed from testosterone-414C. Further, to test whether or not chlormadinone acetate induces the formation of the 5α-reduced derivative of progesterone in the hepatic microsome, we studied the conversion of progesterone-4-14C to 5α-dihydroprogesterone in vitro. The hepatic microsome, which was bubbled through CO gas for 2 min, gave 5α-dihydro-progesterone as the major metabolite of progesterone-4-14C. And the conversion of progesterone to 5α-dihydroprogesterone was also enhanced approximately 3 times by the treatment of chlormadinone acetate (100 mg/kg) for 5 weeks. The hepatic 5α-reductase induced by chlormadinone acetate was able to hydrogenate not only testosterone, but also C21-_??_4-3-oxosteroid such as progesterone. Based on these results, we discussed a regulation system of hepatic testosterone-5α-reduction.
日本内分泌学会の論文

Testosteroneの代謝に及ぼすAnti-androgenの影響 (第II報):肝Testosterone 5α-, 5β-Reductaseに及ぼす各種薬物の効果とその調節因子について

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