ESTROGEN, NOT TESTOSTERONE, CREATES MALE PREDOMINANCE OF A P4501-RELATED CYTOCHROME IN ADULT GUINEA-PIG ADRENALS

Guinea pig adrenal microsomes possess a distinctive cytochrome P450 that is immunochemically related to P4501 and correlates with microsomal capacity for xenobiotic metabolism. This 52K protein and the capacity for metabolizing compounds such as ethylmorphine are located in the tons reticularis, are suppressed by ACTH, and are predominant in adult males. The protein is undetectable and the enzyme activity is low in young prepubertal animals. In males, both increase with age. However, in females, the protein remains undetectable, and ethylmorphine demethylase activity remains low into adulthood. Despite this clear sex difference through puberty and into sexual maturity, we recently observed that in female retired breeders, both the 52K cytochrome P450 and the capacity for metabolism of ethylmorphine appear at levels equal to those in males of comparable age. As estrogen levels are low in female retired breeders, we decided to investigate whether estrogen plays a role in maintaining the low levels of this protein and of xenobiotic metabolism seen in younger females. In a series of gonadectomy and hormone replacement experiments, we demonstrated that estrogen suppressed the levels of both protein and enzyme activity in adult guinea pigs. Ovariectomy resulted in the appearance of the 52K cytochrome P450 and of ethylmorphine demethylase in female adrenal microsomes at levels comparable to those seen in adult males. Estrogen replacement suppressed the increase in both protein concentration and enzyme activity. In hemiovariectomized cycling females, compensatory hypertrophy of the remaining ovary occurred, and the characteristic low levels of the 52K P450 and enzyme activity were maintained. Furthermore, estrogen treatment of male guinea pigs suppressed levels of both the 52K P450 and ethylmorphine demethylase activity in male adrenals. These experiments demonstrate that estrogen plays a significant role in the regulation of this protein. Testosterone, on the other hand, was not required to maintain the higher levels of 52K P450 and correlated enzyme activity in adult males. The levels of both were the same in normal, castrated, and sham-operated males, treated with testosterone or vehicle alone or left untreated. In fact, castration of prepubertal males resulted in a rapid rise to adult male levels of both immunodetectable protein and enzyme activity, implying that some suppressive agent of testicular origin effects the gradual increase that normally occurs with age in males. Taken together, these results indicate that suppression by estrogen is responsible for the low levels of this unique cytochrome P450 and its correlated capacity for xenobiotic metabolism in adrenals of female guinea pigs and that it is the relative lack of such suppression in males, rather than stimulation by testosterone, that accounts for the predominance of both the 52K P4501-related protein and enzyme activity in adult male guinea pig adrenals.