Pascoe G A, Olafsdottir K, Reed D J
Arch Biochem Biophys. 1987 Jul;256(1):150-8. doi: 10.1016/0003-9861(87)90433-4.
Vitamin E protection against chemical-induced toxicity to isolated hepatocytes was examined during an imbalance in the thiol redox system. Intracellular reduced glutathione (GSH) was depleted by two chemicals of distinct mechanisms of action: adriamycin, a cancer chemotherapeutic agent that undergoes redox cycling, producing reactive oxygen species that consume GSH, and ethacrynic acid, a direct depleter of GSH. The experimental system used both nonstressed vitamin E-adequate isolated rat hepatocytes and compromised hepatocytes subjected to physiologically induced stress, generated by incubation in calcium-free medium. At doses whereby intracellular GSH was near total depletion, cell injury induced by either chemical was found to follow the depletion of cellular alpha-tocopherol, regardless of the status of the GSH redox system. Changes in protein thiol contents of the cells closely paralleled the changes in alpha-tocopherol contents throughout the incubation period. Supplementation of the calcium-depleted hepatocytes with alpha-tocopheryl succinate (25 microM) markedly elevated their alpha-tocopherol content and prevented the toxicities of both drugs. The prevention of cell injury and the elevation in alpha-tocopherol contents were both associated with a prevention of the loss in cellular protein thiols in the near total absence of intracellular GSH. The mechanism of protection by vitamin E against chemical-induced toxicity to hepatocytes may therefore be an alpha-tocopherol-dependent maintenance of cellular protein thiols.
在硫醇氧化还原系统失衡期间，研究了维生素E对化学诱导的离体肝细胞毒性的保护作用。通过两种作用机制不同的化学物质消耗细胞内的还原型谷胱甘肽（GSH）：阿霉素，一种进行氧化还原循环的癌症化疗药物，产生活性氧消耗GSH；以及依他尼酸，一种直接消耗GSH的物质。实验系统使用了未受应激且维生素E充足的离体大鼠肝细胞，以及通过在无钙培养基中孵育产生生理诱导应激的受损肝细胞。在细胞内GSH接近完全耗尽的剂量下，发现两种化学物质诱导的细胞损伤均随着细胞α-生育酚的耗尽而发生，而与GSH氧化还原系统的状态无关。在整个孵育期间，细胞蛋白质硫醇含量的变化与α-生育酚含量的变化密切平行。用琥珀酸α-生育酚（25μM）补充缺钙的肝细胞可显著提高其α-生育酚含量，并预防两种药物的毒性。在细胞内GSH几乎完全缺乏的情况下，预防细胞损伤和提高α-生育酚含量均与预防细胞蛋白质硫醇的损失有关。因此，维生素E对化学诱导的肝细胞毒性的保护机制可能是α-生育酚依赖性维持细胞蛋白质硫醇。
