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Hormonal Regulation of Liver Cytochrome P450 Enzymes

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Cytochrome P450

Abstract

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.

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Abbreviations

CIS:

cytokine-inducible SH2-containing protein

CYP:

cytochrome P450

GH:

growth hormone

GHR:

GH receptor

HNF:

hepatocyte nuclear factor

3MC:

3-methylcholanthrene

MSG:

monosodium glutamate

SOCS:

suppressor of cytokine signaling protein

STAT:

signal transducer and activator of transcription.

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Acknowledgment

Studies carried out in the laboratory of DJW were supported in part by National Institutes of Health grant DK33765.

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  1. Division of Cell and Molecular Biology, Department of Biology, Boston University, 5 Cummington Street, 02215, Boston, MA, USA

    Dr. Prof. David J. Waxman

  2. Faculty of Pharmaceutical Sciences, The University of British Columbia, 2405 Westbrook Mall, V6T 1Z3, Vancouver, BC, Canada

    Thomas K. H. Chang

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Correspondence to David J. Waxman .

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  1. University of California, San Francisco, San Francisco, California, USA

    Paul R. Ortiz de Montellano

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Waxman, D., Chang, T. (2015). Hormonal Regulation of Liver Cytochrome P450 Enzymes. In: Ortiz de Montellano, P. (eds) Cytochrome P450. Springer, Cham. https://doi.org/10.1007/978-3-319-12108-6_11

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  • DOI: https://doi.org/10.1007/978-3-319-12108-6_11

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-12107-9

  • Online ISBN: 978-3-319-12108-6

  • eBook Packages: MedicineMedicine (R0)

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