Khan S, O'Brien P J
Faculty of Pharmacy, University of Toronto, 19 Russell Street, Toronto, Ontario, M5S 2S2, Canada.
Biochem Biophys Res Commun. 1997 Sep 18;238(2):320-2. doi: 10.1006/bbrc.1997.7281.
Hypoxia caused the efflux of glutathione (GSH) from hepatocytes before membrane lysis occurred. Dithiothreitol (DTT), a thiol reductant, greatly increased the hypoxia induced GSH efflux as well as the subsequent membrane lysis. The NADH generating nutrients sorbitol and beta-hydroxybutyrate as well as ethanol also enhanced hepatocyte GSH efflux and cell injury, whereas on the other hand NADH oxidising metabolic intermediates, e.g., acetoacetate or the artificial electron acceptor methylene blue, partly prevented GSH efflux and membrane lysis. Hypoxia induced GSH efflux and cytotoxicity were also prevented by oxypurinol, a xanthine oxidase inhibitor, as well as by the polyphenolic antioxidant quercetin, suggesting that reactive oxygen species contributed to the GSH efflux and cell lysis. The above results suggest that reductive stress caused by hypoxia activates the redox sensitive sinusoidal GSH transporter that is likely responsible for the GSH efflux before membrane lysis ensues.
在细胞膜裂解发生之前，缺氧导致肝细胞内谷胱甘肽（GSH）外流。硫醇还原剂二硫苏糖醇（DTT）极大地增加了缺氧诱导的GSH外流以及随后的细胞膜裂解。生成NADH的营养物质山梨醇和β-羟基丁酸以及乙醇也增强了肝细胞GSH外流和细胞损伤，而另一方面，氧化NADH的代谢中间体，如乙酰乙酸或人工电子受体亚甲蓝，则部分地阻止了GSH外流和细胞膜裂解。黄嘌呤氧化酶抑制剂氧嘌呤醇以及多酚类抗氧化剂槲皮素也能阻止缺氧诱导的GSH外流和细胞毒性，这表明活性氧参与了GSH外流和细胞裂解过程。上述结果表明，缺氧引起的还原应激激活了对氧化还原敏感的肝血窦GSH转运体，该转运体可能是细胞膜裂解之前GSH外流的原因。
