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ToxSci Advance Access published online on August 27, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg220
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received June 26, 2003; accepted August 11, 2003
© 2003 Society of Toxicology

Systems Toxicology

Role of Lipid Peroxidation as Mechanism of Liver Injury after Acetaminophen Overdose in Mice

Tamara R. Knight 1, Marc W. Fariss 2, Anwar Farhood 3, and Hartmut Jaeschke 1*

1 Liver Research Institute, University of Arizona, College of Medicine, Tucson, AZ 85724; Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205
2 Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164
3 Department of Pathology, University of Texas Health Science Center, Houston, TX 77030

* To whom correspondence should be addressed. E-mail: jaeschke{at}email.arizona.edu.


  Abstract

Mitochondrial oxidant stress and peroxynitrite formation have been implicated in the pathophysiology of acetaminophen (AAP)-induced liver injury. Therefore, we tested the hypothesis that lipid peroxidation (LPO) might be involved in the injury mechanism. Male C3Heb/FeJ mice fed a high vitamin E-diet (1 g d-{alpha}-tocopheryl acetate/kg diet) for 1 week had 6.7-fold higher hepatic tocopherol levels than animals on the control diet (8.2±0.1 nmol/g liver). Treatment of fasted mice with 300 mg/kg AAP caused centrilobular necrosis with high plasma alanine aminotransferase (ALT) activities at 6 h (3280±570 U/L) but no evidence of LPO (hepatic malondialdehyde, 4-hydroxynonenal). Animals on the vitamin E diet had similar injury and LPO as mice on the control diet. To verify a potential effect of the vitamin E-diet on drug-induced liver injury, animals were pretreated with a combination of phorone, FeSO4 and allyl alcohol. Two h after allyl alcohol, massive LPO and liver injury was observed in livers of animals on the control diet as indicated by a 32-fold increase in malondialdehyde levels, extensive staining for 4-hydroxynonenal, and ALT activities of 2310±340 U/L. Animals on the vitamin E-diet had 40% lower hepatic malondialdehyde levels and 85% lower ALT values. Similar results were obtained when animals were treated for 3 days with {alpha}- or {gamma}-tocopherol (0.19 mmol/kg; ip). Both treatments reduced LPO and injury after allyl alcohol but had no effect on AAP hepatotoxicity. Thus, despite the previously shown mitochondrial oxidant stress and peroxynitrite formation, LPO does not appear to be a critical event in AAP-induced hepatotoxicity.

Key Words: acetaminophen, allyl alcohol, lipid peroxidation, vitamin E, {alpha}-tocopherol, {gamma}-tocopherol .


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