US EPA

7422867 

Journal Article 

Hormonal Regulation of Liver Cytochrome P450 Enzymes 

Waxman, DJ; Chang, TKH; , 

2015 

Springer International Publishing 

Cham 

Cytochrome P450 

813-850 

10.1007/978-3-319-12108-6_11 

http://link.springer.com/10.1007/978-3-319-12108-6_11
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Sex differences characterize hepatic expression of specific cytochrome P450 (CYP) enzymes and their associated CYP genes, and underlie the widespread sex differences in drug and xenobiotic metabolism and toxicity seen in animal models and in humans. Sex differences in P450 expression first emerge around puberty, as exemplified by the postnatal developmental expression patterns characterizing the prototypic sex-specific rat P450 enzymes CYP2C11 (male-specific) and CYP2C12 (female-specific). The sex-dependent expression of liver CYPs is primarily determined by sex differences in the temporal patterns of pituitary growth hormone secretion, which confer widespread sex differences in chromatin accessibility, epigenetic marks, and chromatin states. Mechanistic studies have identified an intracellular signaling protein and transcription factor known as signal transducer and activator of transcription 5b (STAT5b) as a major molecular mediator of the action of growth hormone on the sex-dependent transcription of liver CYP genes. Gonadal hormones (testosterone and estrogen) regulate hepatic expression of sex-dependent P450 enzymes primarily by indirect mechanisms, via gonadal hormone effects on the hypothalamic–pituitary axis, which in turn dictate the sex-dependent temporal pattern of pituitary growth hormone secretion. The expression of sex-dependent liver P450 enzymes can also be altered by hormonal perturbation induced by drugs and other xenobiotics, disease states, including diabetes mellitus, liver cirrhosis, and kidney failure, and dietary factors such as vitamin A.