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.

Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice

“…42,43 Recent studies have shown that up-regulating HO-1 in Kupffer cells by means of overexpression or by pharmacological activators prevents alcohol-induced release of inflammatory mediators by Kupffer cells. 31,41 However, characterization of HO-1 inducers in Kupffer cells remains poorly documented. Our data identify HO-1 as a novel target of CB2 receptors, as shown both in vitro and in vivo.…”

Hepatic Overexpression of Heme Oxygenase-1 Improves Liver Allograft Survival by Expanding T Regulatory Cells

“…However, most of the previous studies have used HO-1 inducers to up-regulate the expression of HO-1 in transplant recipients. The shortcoming of this method is obvious, as the entire body of the recipient becomes exposed to HO-1 after systemic administration of the inducer [4]. Further, the treatment requires substantial amounts of the inducer agent for an extended period after organ grafting.…”

“…It has attracted particular interest due to its extensive physiological functions, and potential therapeutic application [4]. A number of studies have demonstrated that HO-1 and its products display anti-inflammatory [5], anti-oxidative [6] and antiapoptotic [7,8] activities.…”

Elucidating the Role of Biliverdin Reductase in the Expression of Heme Oxygenase-1 as a Cytoprotective Response to Stress

“…In another in vitro study, the protective effect of the flavonoid, quercetin, on the hepatotoxicity of ethanol was attributed to its induction of HO-1 in hepatocytes because the effects of quercetin were abrogated by treatment with zinc mesoporphyrin (Yao et al, 2009). Addition of free iron increased the damage caused by ethanol, whereas CO treatment protected the cells from ethanol-induced toxicity.…”