title: Pregnane X Receptor-Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity.
abstract: Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females.
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (K.S., A.A.G., S.T.Y., R.M.R., M.A.G.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (F.J.G.).
authors.forename: Krisstonia
authors.initials: K
authors.lastname: Spruiell
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (K.S., A.A.G., S.T.Y., R.M.R., M.A.G.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (F.J.G.).
authors.forename: Afua A
authors.initials: AA
authors.lastname: Gyamfi
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (K.S., A.A.G., S.T.Y., R.M.R., M.A.G.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (F.J.G.).
authors.forename: Susan T
authors.initials: ST
authors.lastname: Yeyeodu
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (K.S., A.A.G., S.T.Y., R.M.R., M.A.G.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (F.J.G.).
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Richardson
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (K.S., A.A.G., S.T.Y., R.M.R., M.A.G.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (F.J.G.).
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina (K.S., A.A.G., S.T.Y., R.M.R., M.A.G.); and Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland (F.J.G.) mgyamfi@nccu.edu.
authors.forename: Maxwell A
authors.initials: MA
authors.lastname: Gyamfi
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000428:Alcohol Drinking / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D019938:Cyclin D1 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000378:metabolism*; D012727:Sex Characteristics
chemical_list: D047628:Estrogen Receptor alpha; C000625852:NR1I2 protein, human; C000625853:Nr1i2 protein, mouse; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D019938:Cyclin D1; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial