Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes
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) 4alpha, 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.
SourceAvailable from: Juergen Borlak[Show abstract] [Hide abstract]
ABSTRACT: Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic "harm" caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs' physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals' risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine. Copyright © 2015. Published by Elsevier B.V.Journal of Hepatology 04/2015; 52. DOI:10.1016/j.jhep.2015.04.016 · 10.40 Impact Factor
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ABSTRACT: Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in human need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36h) on CYP450-mediated drug metabolism. In a randomized cross-over study design, nine healthy subjects ingested a cocktail consisting of five CYP-specific probe-drugs (caffeine [CYP1A2], S-warfarin [CYP2C9], omeprazole [CYP2C19], metoprolol [CYP2D6] and midazolam [CYP3A4]) on two occasions (control study after an overnight fast and after 36h of fasting). Blood samples were drawn for pharmacokinetic (PK) analysis using nonlinear mixed effects modeling (NONMEM). In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of CYP-isoforms corresponding with the five studied CYP-enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (p=0.03) and decreased oral S-warfarin clearance by 25% (p<0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, CYP3A4 (p<0.05) and decreased the mRNA expression of the ortholog of CYP2C9 (p<0.001) compared to the post-absorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a non-uniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans. The American Society for Pharmacology and Experimental Therapeutics.Drug metabolism and disposition: the biological fate of chemicals 03/2015; 43(6). DOI:10.1124/dmd.114.062299 · 3.33 Impact Factor
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ABSTRACT: As sex determines mammalian development, understanding the nature and developmental dynamics of the sexually dimorphic transcriptome is important. To explore this, we generated 76 genome-wide RNA-seq profiles from mouse eight-cell embryos, late gestation and adult livers, together with 4 ground-state pluripotent embryonic (ES) cell lines from which we generated both RNA-seq and multiple ChIP-seq profiles. We complemented this with previously published data to yield 5 snap-shots of pre-implantation development, late-gestation placenta and somatic tissue and multiple adult tissues for integrative analysis. We define a high-confidence sex-dimorphic signature of 69 genes in eight-cell embryos. Sex-chromosome-linked components of this signature are largely conserved throughout pre-implantation development and in ES cells, whilst the autosomal component is more dynamic. Sex-biased gene expression is reflected by enrichment for activating and repressive histone modifications. The eight-cell signature is largely non-overlapping with that defined from fetal liver, neither was it correlated with adult liver or other tissues analysed. The number of sex-dimorphic genes increases throughout development. We identified many more dimorphic genes in adult compared to fetal liver. However, approximately two thirds of the dimorphic genes identified in fetal liver were also dimorphic in adult liver. Sex-biased expression differences unique to adult liver were enriched for growth hormone-responsiveness. Sexually dimorphic gene expression in pre-implantation development is driven by sex-chromosome based transcription, whilst later development is characterised by sex dimorphic autosomal transcription. This systematic study identifies three distinct phases of sex dimorphism throughout mouse development, and has significant implications for understanding the developmental origins of sex-specific phenotypes and disease in mammals.BMC Genomics 04/2015; 16(1):295. DOI:10.1186/s12864-015-1506-4 · 4.04 Impact Factor