Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, MA 02215, USA.
Molecular pharmacology (Impact Factor: 4.13). 06/2009; 76(2):215-28. DOI: 10.1124/mol.109.056705
Source: PubMed


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.

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    • "Nevertheless, dimorphic patterns of rats have been fairly mirrored in humans. For instance, differences in xenobiotic metabolism (Waxman and Holloway, 2009), liver fibrosis (Yasuda et al., 1999) or even in a basic parameter like liver weight have been described. "
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    ABSTRACT: It was shown recently that many genes are differentially expressed in the liver of males and females, thus strengthening the concept of liver gender dimorphism. This dimorphism exists in many pathological scenarios, from regeneration to fibrosis, which has led to the development of gender hepatology. Nevertheless, it is still unknown if gender dimorphism occurs in the structure of the normal liver. In recent years, it has been shown that, compared with male, the female rat liver bears less fibrotic tissue, more Kupffer cells (per volume unit) and has higher hepatocellularity, including binucleated hepatocytes (per volume unit). Our hypothesis is that the human liver also hides a gender dimorphic pattern. Baseline differences in fibrotic tissue would contribute to explain severe liver fibrosis in men. As to the disparity of Kupffer cells, this would clarify the stronger response to post-surgery infections in women, and it could be equated when appraising the higher susceptibility to alcohol. Regarding differences in hepatocytes, they not only justify existing differences in some liver parameters (e.g., transaminases and bilirubin), but they could also account for the higher regenerative potential of the female liver. The structural dimorphism in the human liver would sustain the concept of gender hepatology and, eventually, should be considered in the context of liver transplantation.
    Histology and histopathology 07/2015; 30(12):11648. DOI:10.14670/HH-11-648 · 2.10 Impact Factor
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    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(2). DOI:10.1016/j.jhep.2015.04.016 · 11.34 Impact Factor
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    • "The main reason that could explain these differences seems to be the different expression profiles of metabolizing enzymes and efflux transporters in the main metabolic disposition organs, such as the intestine, liver, and kidney [22]. In other studies, pulsatile versus continuous release of growth hormone in male and female rats, respectively, has been suggested as a major reason for the sex-dependent differences in the expression profiles of the hepatic phase I metabolizing enzymes [23]. Summarizing, our study showed that HT and its metabolites could be accumulated in a dose-dependent manner basically in the liver, kidney and brain and were detected in these tissues even at nutritionally relevant human dose, a dose that was not previously studied in tissue disposition. "
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    ABSTRACT: Hydroxytyrosol (HT) is the most prominent phenolic compound of virgin olive oil and due to its scientifically validated biological activities it is entering to the market as a potentially useful supplement for cardiovascular disease prevention. The aim of the present study was to investigate the relationship between the HT dose intake and its tissue uptake in rats, and thus, providing complementary information in relation to the target-dose relationship. Rats were given a refined olive oil enriched with HT at different doses (1, 10 and 100 mg/kg) and they were sacrificed after 5 h to ensure the cell tissue uptake of HT and its metabolites. Plasma samples and different organs as liver, kidney, heart and brain were obtained, and HT metabolites were analyzed by UPLC-MS/MS. The results showed that HT and its metabolites could be accumulated in a dose-dependent manner basically in the liver, kidney and brain and were detected in these tissues even at nutritionally-relevant human doses. The detection of free HT in liver and kidney is noteworthy. To date, this appears to be the only biologically active form, and thus, it provides relevant information for optimizing the potential applications of HT to prevent certain hepatic and renal diseases. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Molecular Nutrition & Food Research 03/2015; 59(7). DOI:10.1002/mnfr.201500048 · 4.60 Impact Factor
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