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ToxSci Advance Access originally published online on August 27, 2003
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Toxicological Sciences 76, 229-236 (2003)
Copyright © 2003 by the Society of Toxicology

SYSTEMS TOXICOLOGY

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

Tamara R. Knight*,{dagger}, Marc W. Fariss{ddagger}, Anwar Farhood§ and Hartmut Jaeschke*,{dagger},1

* Liver Research Institute, College of Medicine, University of Arizona, Tucson, Arizona 85724; {dagger} Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205; {ddagger} Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington 99164; and § Department of Pathology, University of Texas Health Science Center, Houston, Texas 77030

Mitochondrial oxidant stress and peroxynitrite formation have been implicated in the pathophysiology of acetaminophen-induced (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 diet high in vitamin E (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. We observed, 2 h after allyl alcohol, massive LPO and liver cell injury in the 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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