Sexually Dimorphic Regulation of Hepatic Isoforms of Human Cytochrome P450 by Growth Hormone

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Abstract
Sex differences in drug metabolism have been reported in numerous species, including humans. In rats and mice, sex-dependent differences in circulating growth hormone profiles are responsible for the differential expression of multiple sex-dependent isoforms of cytochrome P450, which is the basis for the sexual dimorphism in drug metabolism. In contrast, very little is known about sex differences in human isoforms of cytochrome P450 and their regulation by growth hormone. In this study, we have examined the effects of physiologic-like exposure doses to dexamethasone and/or pulsatile (masculine) or constant (feminine) human growth hormone on expression levels of CYP3A4, 1A2, 2D6, and 2E1 and the glucocorticoid and growth hormone receptors in hepatocyte cultures obtained from men and women donors. We report that growth hormone can regulate expression of CYP3A4, 1A2, and 2D6. The masculine-like pulsatile growth hormone profile suppresses dexamethasone-induced CYP3A4, 1A2, and 2D6, whereas the feminine-like constant profile is permissive allowing isoform expression to be equal to or greater than glucocorticoid induction alone. There are intrinsic sexual differences in hepatocytes of men and women resulting in different levels of responsiveness of CYP3A4, 1A2, and hormone receptor expression to the same sexually dimorphic growth hormone profiles. Last, although real, the sexually dimorphic effects of growth hormone on human cytochrome P450 expression are not as dramatic as those observed in rats and could easily be overlooked by the heterogeneous backgrounds of human populations.