Intrinsic Sexually Dimorphic Expression of the Principal Human CYP3A4 Correlated with Suboptimal Activation of GH/Glucocorticoid-Dependent Transcriptional Pathways in Men

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Abstract

Cytochrome P450 (CYP)3A4 is the principal and most abundant human isoform of CYP responsible for the metabolism of more than 50% of all consumed drugs and innumerable endogenous compounds. Expression of CYP3A4 is sexually dimorphic and regulated by the combined actions of GH and glucocorticoids. In the case of the rat, nearly all of the CYPs are “intrinsically” or “inherently” sexually dimorphic, meaning that the expressed sex differences are permanent and irreversible. Using primary hepatocyte cultures derived from men and women exposed to physiologic-like levels of continuous GH (the feminine circulating profile) alone, dexamethasone alone, and the combined regimen, we observed a dramatic inherent CYP3A4 sexual dimorphism (women more than men) with all treatments. The molecular basis for this intrinsic sexually dimorphic expression of CYP3A4 appears to be due, at least in part, to a greater level of hormone-dependent activation and nuclear translocation of both hepatocyte nuclear factor-4α (HNF-4α) and pregnane X receptor in female hepatocytes. Furthermore, these transcription factors exhibited significantly higher DNA binding levels to their specific motifs on the CYP3A4 promoter in female hepatocytes, inferring a possible explanation for the elevated expression of CYP3A4 in women. Accordingly, experiments using HepG2 cells treated with small inhibitory RNA-induced knockdown of HNF-4α and/or transfected with luciferase reporter constructs containing a CYP3A4 promoter lacking HNF-4α-binding motifs demonstrated that GH, to a greater extent dexamethasone, and to the greatest extent the combine hormone regimen, stimulated HNF-4α and pregnane X receptor promoter transactivation, signifying enhanced transcription of CYP3A4 and, thus, identifying a molecular mechanism contributing to the intrinsic sexual dimorphic expression of human CYP3A4.

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