Yao Ping, Nussler Andreas, Liu Liegang, Hao Liping, Song Fangfang, Schirmeier Anja, Nussler Natascha
Department of General-, Visceral-, and Transplantation Surgery, Humboldt University, Charité, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany.
J Hepatol. 2007 Aug;47(2):253-61. doi: 10.1016/j.jhep.2007.02.008. Epub 2007 Mar 7.
BACKGROUND/AIMS: Flavonoids, including quercetin, have been reported to have potent hepatoprotective effects, which may be associated with HO-1 induction. However, since the effect and signaling pathway of quercetin involved in HO-1 induction against alcoholic liver damage are still not fully understood, this is the target of the present study.
Human hepatocytes were incubated with ethanol (100 mM) and quercetin (10-200 microM), and cellular damage and HO-1 activity were measured. Nrf2 expression in cytosolic and nuclear fractions was studied following the incubation with MAPK inhibitor(s).
Ethanol exposure resulted in a sustained glutathione depletion, malondialdehyde elevation, and evident release of cellular LDH and AST. Quercetin exerted a dose-dependent protective effect against alcoholic oxidative stress, and increased the EC50 of ethanol by approx. 40%, which is parallel to HO-1 induction with quercetin. Zinc protoporphyrin-9 abrogated the protective effect and dramatically enhanced ethanol cytotoxicity. SB203580 (p38 inhibitor) and especially PD98059 (ERK inhibitor) blocked quercetin-derived HO-1 induction and Nrf2 translocation, and subsequently inhibited the quercetin-related protection.
HO-1 up-regulation by quercetin protected human hepatocytes from ethanol-induced oxidative stress. Among MAPK signaling pathways, p38 and ERK mediated quercetin-derived Nrf2 translocation into nuclei and subsequent induction of HO-1 activity, and the latter showed a stronger mediating effect.
背景/目的：据报道，包括槲皮素在内的黄酮类化合物具有强大的肝脏保护作用，这可能与诱导血红素加氧酶-1（HO-1）有关。然而，由于槲皮素诱导HO-1对酒精性肝损伤的作用及信号通路仍未完全明确，本研究以此为目标。
将人肝细胞与乙醇（100 mM）和槲皮素（10 - 200 μM）共同孵育，检测细胞损伤及HO-1活性。在用丝裂原活化蛋白激酶（MAPK）抑制剂孵育后，研究细胞质和细胞核组分中核因子E2相关因子2（Nrf2）的表达。
乙醇暴露导致谷胱甘肽持续耗竭、丙二醛升高以及细胞乳酸脱氢酶（LDH）和天冬氨酸转氨酶（AST）明显释放。槲皮素对酒精性氧化应激发挥剂量依赖性保护作用，并使乙醇的半数有效浓度（EC50）提高约40%，这与槲皮素诱导HO-1的作用平行。锌原卟啉-9消除了保护作用并显著增强乙醇细胞毒性。SB203580（p38抑制剂）尤其是PD98059（细胞外信号调节激酶（ERK）抑制剂）阻断了槲皮素诱导的HO-1表达及Nrf2易位，随后抑制了槲皮素相关的保护作用。
槲皮素上调HO-1可保护人肝细胞免受乙醇诱导的氧化应激。在MAPK信号通路中，p38和ERK介导了槲皮素诱导的Nrf2易位至细胞核及随后HO-1活性的诱导，且ERK显示出更强的介导作用。
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