Regulation of ethanol-induced toxicity by mitochondrial NADP(+)-dependent isocitrate dehydrogenase.
Chronic alcohol administration has been known to increase peroxynitrite hepatotoxicity by enhancing concomitant production of nitric oxide and superoxide. We previously reported that control of the mitochondrial redox balance and the cellular defense against oxidative damage are primary functions of mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDPm) through to supply NADPH for antioxidant systems. In the present study, we demonstrate that modulation of IDPm expression in HepG2 cells regulates ethanol-induced toxicity. We observed the significantly enhanced protection to cell killing, lipid peroxidation, protein oxidation, oxidative DNA damage, and decrease in generation of intracellular reactive oxygen species and reactive nitrogen species in IDPm-overexpressed cells compared to control cells upon exposure to ethanol. In contrast, transfection of HepG2 cells with IDPm short interfering RNA markedly decreased the expression of IDPm, modulating cellular redox status and subsequently enhancing the susceptibility of ethanol-induced toxicity. These studies support the hypothesis that IDPm plays an important role in regulating the toxicity induced by ethanol presumably through maintaining the cellular redox status.
Yang
Eun Sun
ES
Kyungpook National University, Taegu, Republic of Korea.
Park
Jeen-Woo
JW
D000595:Amino Acid Sequence; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D000431:Ethanol / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014162:Transfection
D000975:Antioxidants; D018076:DNA, Complementary; D034741:RNA, Small Interfering; D030421:Peroxynitrous Acid; D000431:Ethanol; D007521:Isocitrate Dehydrogenase; C039355:isocitrate dehydrogenase (NADP+); D019392:Cytochrome P-450 CYP2E1