Self-augmentation effect of male-specific products on sexually differentiated progesterone metabolism in adult male rat liver microsomes

It is well known that several 3-keto-4-ene steroids such as progesterone an d testosterone are metabolized in a gender-specific or -predominant manner by adult rat liver microsomes. In the male, these steroids are primarily me tabolized into two oxidized (16 alpha -hydroxyl and 6 beta -hydroxyl) produ cts mainly by the respective, male-specific cytochrome P450 subforms, CYP2C 11 and CYP3A2, while they are primarily metabolized into the 5 alpha -reduc ed products by female-predominant 5 alpha -reductase in the female. These s exually differentiated enzyme activities are largely regulated at the trans cription level under endocrine control. In the present study, we show that unlabeled 16 alpha -hydroxyprogesterone and 6 beta -hydroxyprogesterone inh ibited the 5 alpha -reductive [H-3]progesterone metabolism by adult male ra t liver microsomes without significantly inhibiting the CYP2C11 and CYP3A2 activities producing themselves, whereas 3 alpha -hydroxy-5 alpha -pregnan- 20-one and 5 alpha -pregnane-3,20-dione not only stimulated the 5 alpha -re ductive metabolism producing themselves but also inhibited the male-specifi c oxidative metabolism. This finding compels us to propose a novel hypothes is that adult male rat liver microsomes may possess a self-augmentation sys tem regulated by the male-specific products on sexually differentiated ster oid metabolism, besides regulation by gene expressions of the related enzym es.