Acetaminophen toxicity - Opposite effects of two forms of glutathione peroxidase

Acetaminophen is one of the most extensively used analgesics/antipyretics w orldwide, and overdose or idiopathic reaction causes major morbidity and mo rtality in its victims. Research into the mechanisms of toxicity and possib le therapeutic intervention is therefore essential. In this study, the resp onse of transgenic mice overexpressing human antioxidant enzymes to acute a cetaminophen overdose was investigated. Animals overexpressing superoxide d ismutase or plasma glutathione peroxidase demonstrated dramatic resistance to acetaminophen toxicity. Intravenous injection of glutathione peroxidase provided normal mice with nearly complete protection against a lethal dose of acetaminophen. Surprisingly, animals overexpressing intracellular glutat hione peroxidase in the liver were significantly more sensitive to acetamin ophen toxicity compared with nontransgenic littermates. This sensitivity ap pears to be due to the inability of these animals to efficiently recover gl utathione depleted as a result of acetaminophen metabolism. Finally, the re sults suggest that glutathione peroxidase overexpression modulates the synt hesis of several acetaminophen metabolites. Our results demonstrate the abi lity of glutathione peroxidase levels to influence the outcome of acetamino phen toxicity.