Cytochrome P450s in the Guinea Pig Adrenal That Are Immunologically Similar to Liver Forms: Estrogen Suppression Explains Male-female Differences

Several cytochrome P450s have been identified in guinea pig adrenal microsomes which are distinct from the known steroidogenic P450s, c17 and c21, and are immunochemically related to cytochrome P450s found in liver. One, a 52 K protein related to P450 I (CYP1), occurs almost exclusively in males, is localized to the inner zone, and is suppressed by ACTH. Its levels correlate with microsomal capacity for xenobiotic metabolism. The others, related to P450s II and III (CYP2 and 3), are more predominant in males, but not exclusive to them, are found in both the inner and outer zones, and are not suppressed by ACTH. Their functions remain to be elucidated. The male predominance of the CYP1-related protein has recently been shown to be due to suppression of the protein in females by estrogen. To determine if estrogen is also involved in the regulation of the CYP2-related proteins, ovariectomized and sham-operated animals were treated with a long-acting estrogen, estradiol valerate, or with the vehicle alone. These P450s reached male levels in ovariectomized females treated only with the vehicle. Their enhanced levels were suppressed by treatment with estrogen. Estrogen treatment also suppressed the levels of the P450s seen in sham-operated females. Endogenous estrogen produced similar effects. In hemi-ovariectomized females the contralateral ovary hypertrophied, a state in which estrogen levels would be maintained or increased. In these females no increase occurred in the immunodetectable P450s. In normal females, estrogen levels are low in prepubertal animals, rise at the time of puberty and drop again after ovarian cycling is completed. The CYP2-related proteins were present in adrenal microsomes of prepubertal females, but were suppressed after puberty. On the other hand, post-estrous females, in whom estrogen levels would be low, acquired male levels of these proteins in their adrenal microsomes. P450c17 and P450c21, as well as 3β-hydroxysteroid dehydrogenase, were not affected by surgery or estrogen. Taken together, these experiments indicate that suppression by estrogen in females can account, in large part, for the predominance of several immunochemical homologs of liver P450s in adult male guinea pig adrenals.