The role of iron and glutathione in t-butyl hydroperoxide-induced damage towards isolated perfused rat livers.

The hepatotoxic and lipid peroxidative potentials of t-butyl hydroperoxide (t-BuOOH) towards isolated perfused rat livers were investigated at doses of 1 and 3 mmol l-1. t-BuOOH led to a concentration-dependent release of cytosolic (glutamate-pyruvate transaminase and lactate dehydrogenase) and mitochondrial (glutamate dehydrogenase) enzymes, an accumulation of calcium in the liver, a marked depletion of hepatic glutathione and an enhanced release of it into the perfusate, as well as an enhanced formation and release of malondialdehyde (MDA) by the liver. These effects were blocked in the presence of the potent iron chelator deferrioxamine, and enhanced in livers from iron-overloaded as well as in livers from glutathione-depleted rats. Our results indicate that the hepatotoxic and pro-oxidant actions of organic hydroperoxides depend upon the presence of ionized iron as a catalyst of radical-forming breakdown reactions, and are potentiated by impairment of glutathione-dependent detoxification reactions.