title: Quercetin suppressed CYP2E1-dependent ethanol hepatotoxicity via depleting heme pool and releasing CO.
abstract: Naturally occuring quercetin protects hepatocytes from ethanol-induced oxidative stress, and heme oxygenase-1 (HO-1) induction and carbon monoxide (CO) metabolite may be implicated in the beneficial effect. However, the precise mechanism by which quercetin counteracts CYP2E1-mediated ethanol hepatotoxicity through HO-1 system is still remained unclear. To explore the potential mechanism, herein, ethanol (4.0 g/kg.bw.) was administrated to rats for 90 days. Our data showed that chronic ethanol over-activated CYP2E1 but suppressed HO-1 with concurrent hepatic oxidative damage, which was partially normalized by quercetin (100mg/kg.bw.). Quercetin (100 μM) induced HO-1 and depleted heme pool when incubated to human hepatocytes. Ethanol-stimulated (100mM) CYP2E1 upregulation was suppressed by quercetin but further enhanced by HO-1 inhibition with resultant heme accumulation. CO scavenging blocked the suppression of quercetin only on CYP2E1 activity. CO donor dose-dependently inactivated CYP2E1 of ethanol-incubated microsome, which was mimicked by HO-1 substrate but abolished by CO scavenger. Thus, CYP2E1-mediated ethanol hepatotoxicity was alleviated by quercetin through HO-1 induction. Depleted heme pool and CO releasing limited protein synthesis and inhibited enzymatic activity of CYP2E1, respectively.
authors.affiliation: Department of Nutrition and Food Hygiene and MOE Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Tang
authors.forename: Hongtao
authors.initials: H
authors.lastname: Tian
authors.forename: Yanru
authors.initials: Y
authors.lastname: Shi
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.forename: Mingyou
authors.initials: M
authors.lastname: Xing
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Bao
authors.forename: Di
authors.initials: D
authors.lastname: Wang
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism*; D002478:Cells, Cultured; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D020011:Protective Agents; D000431:Ethanol; D006418:Heme; D002248:Carbon Monoxide; D011794:Quercetin; D019392:Cytochrome P-450 CYP2E1; D051547:Heme Oxygenase-1