Abstract
Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4α, as mediators of the sex-dependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.
Footnotes
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↵1 Although the term “gender differences” is often used in the medical literature to describe male-female differences, “sex” is the preferred term when describing biologically determined physiological, or pathophysiological, differences between male and female members of a species. “Gender” is a social construct that refers to an individual's self-representation as masculine or feminine, which, unlike “sex,” can be influenced by cultural factors (Gray, 2007).
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This work was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK33765].
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ABBREVIATIONS: DME, drug-metabolizing enzyme; P450, cytochrome P450; GH, growth hormone; IGF, insulin-like growth factor; STAT, signal transducer and activator of transcription; JAK, Janus kinase; HNF, hepatic nuclear factor.
- Accepted May 29, 2009.
- Received April 1, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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- Abstract
- Sex Differences in Hepatic Drug Metabolism
- Gonadal and Pituitary Hormonal Determinants of Hepatic Sex Differences
- Class I and Class II Sex-Specific Genes
- Requirement of STAT5b for the Sex-Dependent Actions of GH
- Potential Limitations of the Global STAT5b-Deficient Mouse Model
- STAT5-Dependent Sex Differences in Postnatal Growth
- Impact of Liver-Specific Hnf4α-Deletion on Sex-Specific Gene Expression
- Mechanisms Whereby STAT5b Regulates Sex-Specific Gene Expression
- Epigenetic Regulation of GH-Responsive Sex-Specific Genes
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