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J. Biol. Chem., Vol. 276, Issue 7, 4604-4610, February 16, 2001

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Self-augmentation Effect of Male-specific Products on Sexually Differentiated Progesterone Metabolism in Adult Male Rat Liver Microsomes^*

Akihiko Yamada^§, Morio Yamada^¶, Yukihisa Fujita^¶, Takashi Nishigami, Keiji Nakasho, and Kunio Uematsu

From the  Second Department of Pathology, and the ^¶ Department of Chemistry, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan

It is well known that several 3-keto-4-ene steroids such as progesterone and testosterone are metabolized in a gender-specific or -predominant manner by adult rat liver microsomes. In the male, these steroids are primarily metabolized into two oxidized (16-hydroxyl and 6-hydroxyl) products mainly by the respective, male-specific cytochrome P450 subforms, CYP2C11 and CYP3A2, while they are primarily metabolized into the 5-reduced products by female-predominant 5-reductase in the female. These sexually differentiated enzyme activities are largely regulated at the transcription level under endocrine control. In the present study, we show that unlabeled 16-hydroxyprogesterone and 6-hydroxyprogesterone inhibited the 5-reductive [³H]progesterone metabolism by adult male rat liver microsomes without significantly inhibiting the CYP2C11 and CYP3A2 activities producing themselves, whereas 3-hydroxy-5-pregnan-20-one and 5-pregnane-3,20-dione not only stimulated the 5-reductive metabolism producing themselves but also inhibited the male-specific oxidative metabolism. This finding compels us to propose a novel hypothesis that adult male rat liver microsomes may possess a self-augmentation system regulated by the male-specific products on sexually differentiated steroid metabolism, besides regulation by gene expressions of the related enzymes.

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