REGULATION OF CYTOCHROME P450'S IN ADRENAL

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In the guinea pig adrenal, the zona reticularis occupies over 50% of the cortical mass in adult males. The ability of the adrenal to metabolize foreign compounds is localized to the microsomes obtained from this zone. This capacity for xenobiotic metabolism increases with age, is greater in males than in females, and is suppressed by ACTH treatment, and is male- specific. This 52K protein does not react with antibodies against known adrenal microsomal steroid hydroxylases (P45021 and P45017alpha), but does react with antibody against methylcholanthrene-induced P450s in rat liver (P450c,d). Several hepatic cytochrome P450s have been shown to hydroxylate androgens at specific sites on the sterol ring, in addition to their capacity for xenobiotic metabolism. Some of these are sex-dependent. This is the first direct indication of a sex-dependent P450 in the adrenal. Whether it is specific for metabolism of foreign compounds or has functions in as yet undescribed male-specific steroid hydroxylation needs to be determined. Its relationship to P450c,d is of particular interest since neither of these proteins is known to be sex-dependent. The inner zone localization of this male-specific cytochrome P450 places it in an ideal position to modify steroids secreted by the outer zone. Its suppression by ACTH could provide an intraadrenal regulator of total steroid output. Analysis of its regulation by gonadal and pituitary hormones needs to be investigated. It is the purpose of this proposal: (1) To define the function of this male-specific P450 in xenobiotic vs steroid metabolism. (2) To investigate regulation of this P450 by gonadal and pituitary hormones at the protein and mRNA levels. (3) To investigate the relationship of this P450 to other members of this gene superfamily by cloning and sequence analysis.