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J Biol Chem, Vol. 274, Issue 15, 10349-10355, April 9, 1999

Acetaminophen Toxicity
OPPOSITE EFFECTS OF TWO FORMS OF GLUTATHIONE PEROXIDASE

Oleg Mirochnitchenko, Miriam Weisbrot-Lefkowitz, Kenneth Reuhl^¶, Laishun Chen, Chung Yang, and Masayori Inouye

From the  Department of Biochemistry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, ^¶ Neurotoxicology Laboratories, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, and  Department of Chemical Biology, Laboratory for Cancer Research, College of Pharmacy, Rutgers University, Piscataway, New Jersey 08854

Acetaminophen is one of the most extensively used analgesics/antipyretics worldwide, and overdose or idiopathic reaction causes major morbidity and mortality in its victims. Research into the mechanisms of toxicity and possible therapeutic intervention is therefore essential. In this study, the response of transgenic mice overexpressing human antioxidant enzymes to acute acetaminophen overdose was investigated. Animals overexpressing superoxide dismutase 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 glutathione peroxidase in the liver were significantly more sensitive to acetaminophen toxicity compared with nontransgenic littermates. This sensitivity appears to be due to the inability of these animals to efficiently recover glutathione depleted as a result of acetaminophen metabolism. Finally, the results suggest that glutathione peroxidase overexpression modulates the synthesis of several acetaminophen metabolites. Our results demonstrate the ability of glutathione peroxidase levels to influence the outcome of acetaminophen toxicity.

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