Jimenez-Lopez Jose M, Cederbaum Arthur I
Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Free Radic Biol Med. 2004 Feb 1;36(3):359-70. doi: 10.1016/j.freeradbiomed.2003.11.016.
Chronic ethanol consumption causes oxidative damage in the liver, and induction of cytochrome P450 2E1 (CYP2E1) is one pathway involved in oxidative stress produced by ethanol. The hepatic accumulation of iron and polyunsaturated fatty acids significantly contributes to ethanol hepatotoxicity in the intragastric infusion model of ethanol treatment. The objective of this study was to analyze the effect of the green tea flavanol epigallocatechin-3-gallate (EGCG), which has been shown to prevent alcohol-induced liver damage, on CYP2E1-mediated toxicity in HepG2 cells overexpressing CYP2E1 (E47 cells). Treatment of E47 cells with arachidonic acid plus iron (AA + Fe) was previously reported to produce synergistic toxicity in E47 cells by a mechanism dependent on CYP2E1 activity and involving oxidative stress and lipid peroxidation. EGCG protected E47 cells against toxicity and loss of viability induced by AA+Fe; EGCG had no effect on CYP2E1 activity. Prevention of this toxicity was associated with a reduction in oxidative damage as reflected by decreased generation of reactive oxygen species, a decrease in lipid peroxidation, and maintenance of intracellular glutathione in cells challenged by AA+Fe in the presence of EGCG. AA+Fe treatment caused a decline in the mitochondrial membrane potential, which was also blocked by EGCG. In conclusion, EGCG exerts a protective action on CYP2E1-dependent oxidative stress and toxicity that may contribute to preventing alcohol-induced liver injury, and may be useful in preventing toxicity by various hepatotoxins activated by CYP2E1 to reactive intermediates.
长期摄入乙醇会导致肝脏氧化损伤，细胞色素P450 2E1（CYP2E1）的诱导是乙醇产生氧化应激所涉及的一条途径。在乙醇处理的灌胃模型中，肝脏中铁和多不饱和脂肪酸的蓄积显著促进了乙醇的肝毒性。本研究的目的是分析绿茶黄烷醇表没食子儿茶素-3-没食子酸酯（EGCG）对过表达CYP2E1的HepG2细胞（E47细胞）中CYP2E1介导的毒性的影响，EGCG已被证明可预防酒精性肝损伤。先前报道，用花生四烯酸加铁（AA + Fe）处理E47细胞会通过一种依赖CYP2E1活性且涉及氧化应激和脂质过氧化的机制在E47细胞中产生协同毒性。EGCG保护E47细胞免受AA+Fe诱导的毒性和活力丧失；EGCG对CYP2E1活性无影响。这种毒性的预防与氧化损伤的减少有关，这表现为活性氧生成减少、脂质过氧化减少以及在EGCG存在下受到AA+Fe攻击的细胞中细胞内谷胱甘肽的维持。AA+Fe处理导致线粒体膜电位下降，这也被EGCG阻断。总之，EGCG对CYP2E1依赖性氧化应激和毒性发挥保护作用，这可能有助于预防酒精性肝损伤，并且可能有助于预防由CYP2E1激活为反应性中间体的各种肝毒素引起的毒性。
