title: The protective role of HO-1 and its generated products (CO, bilirubin, and Fe) in ethanol-induced human hepatocyte damage.
abstract: It has been reported that naturally occurring quercetin exerts hepatoprotective effects through heme oxygenase-1 (HO-1) induction. However, the precise mechanism of how ethanol-associated liver damage is counteracted by quercetin-enhanced HO-1 metabolism still remains unclear. To further decipher the protective role of quercetin on ethanol-induced liver damage, we treated human hepatocytes with quercetin and various (end) products of the HO-1 pathway. Our data clearly showed that quercetin treatment attenuated ethanol-induced damage, whereas hemoglobin and zinc protoporphyrin 9 (ZnPP) abolished such effects. Iron-II aggravated ethanol toxicity and was only partially reduced by quercetin. In contrast, carbon monoxide (CO) dose dependently inhibited ethanol-induced cytochrome P450 2E1 (CYP 2E1) activity and hepatotoxicity but had no influence on CYP 2E1 protein expression. Similarly, hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. ZnPP significantly promoted CYP 2E1 protein expression in the presence and absence of CO treatment but inhibited ethanol-induced CYP 2E1 activation following CO incubation in quercetin- and ethanol-cotreated hepatocytes. These results suggested that quercetin virtually attenuated ethanol-derived oxidative damage via HO-1 induction. Heme degradation and CO release may mediate the protective effects through inhibiting ethanol-induced CYP 2E1 synthesis and enzymatic activity, respectively.
authors.affiliation: Universitätsmedizin Berlin, Charité, Campus Virchow, Department of General, Visceral, and Transplantation Surgery, Berlin, Germany.
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
authors.forename: Liping
authors.initials: L
authors.lastname: Hao
authors.forename: Natascha
authors.initials: N
authors.lastname: Nussler
authors.forename: Antje
authors.initials: A
authors.lastname: Lehmann
authors.forename: Fangfang
authors.initials: F
authors.lastname: Song
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Peter
authors.initials: P
authors.lastname: Neuhaus
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
authors.forename: Andreas
authors.initials: A
authors.lastname: Nussler