Vitamin E succinate protects hepatocytes against the toxic effect of reactive oxygen species generated at mitochondrial complexes I and III by alkylating agents.

The mechanism of alpha-tocopheryl succinate (TS) cytoprotection against mitochondria-derived oxidative stress was investigated. Incubation of isolated rat hepatocytes with ethyl methanesulfonate (EMS), a mitochondrial alkylating toxicant caused mitochondrial dysfunction and necrotic cell death that was dependent on the production of reactive oxygen species (ROS) and lipid peroxidation. Mitochondria isolated from these cells showed a 3-fold increase in lipid hydroperoxides and a selective depletion of alpha-tocopherol (T), which preceded cell death.

Mitochondrial electron transport inhibitors cause lipid peroxidation-dependent and -independent cell death: protective role of antioxidants.

Mitochondrial electron transport inhibitors induced two distinct pathways for acute cell death: lipid peroxidation-dependent and -independent in isolated rat hepatocytes. The toxic effects of mitochondrial complex I and II inhibitors, rotenone (ROT) and thenoyltrifluoroacetone (TTFA), respectively, were dependent on oxidative stress and lipid peroxidation, while cell death induced by inhibitors of complexes III and IV, antimycin A (AA) and cyanide (CN), respectively, was caused by MMP collapse and loss of cellular ATP. Accordingly, cellular and mitochondrial antioxidant depletion or supplementation, in general, resulted in a dramatic potentiation or prevention, respectively, of toxic injury induced by complex I and II inhibitors, with little or no effect on complex III and IV inhibitor-induced toxicity.

Enhanced antioxidant and cytoprotective abilities of vitamin E succinate is associated with a rapid uptake advantage in rat hepatocytes and mitochondria.

Numerous in vitro studies attest to the enhanced ability of vitamin E succinate (TS), as compared with conventional vitamin E compounds such as unesterified d-alpha-tocopherol (T) and d-alpha-tocopheryl acetate (TA), to protect hepatocytes from toxic oxidative stress. In the present study we tested the hypothesis that this unique protective ability is related to an enhanced cellular accumulation of TS. The results of this study indicate, using both in vitro and in vivo model systems, that acute TS administration results in a rapid increase in T and TS content and antioxidant protection of hepatocytes and mitochondria.

Glutathione-dependent regulation of nitric oxide production in isolated rat hepatocyte suspensions.

Freshly isolated suspensions of rat parenchymal liver cells (hepatocytes) spontaneously produce large amounts of nitrite following collagenase isolation. Our previous studies indicate that nitrite production is associated with the expression of inducible nitric oxide synthase (iNOS) and reflects NO production. Depletion of glutathione (GSH) with diethylmaleate (DEM) inhibited nitrite production, and this inhibition was time-dependent.

Clofibrate pretreatment in mice confers resistance against hepatic lipid peroxidation.

Pretreatment with peroxisome proliferators protects mice against various hepatotoxicants. Since our previous work suggested that the hepatoprotection may involve an increased ability to cope with oxidative stress, the present work directly addressed this possibility. Several observations indicated a heightened defense against oxidative stress accompanies the hepatoprotection produced by clofibrate.