ACETAMINOPHEN-INDUCED HEPATOTOXICITY

Laura P. James; Philip R. Mayeux; Jack A. Hinson

doi:10.1124/dmd.31.12.1499

Abstract

The analgesic acetaminophen causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. The initial phases of toxicity were described in Dr. Gillette's laboratory in the 1970s. These findings indicated that acetaminophen was metabolically activated by cytochrome P450 enzymes to a reactive metabolite that depleted glutathione (GSH) and covalently bound to protein. It was shown that repletion of GSH prevented the toxicity. This finding led to the development of the currently used antidote N-acetylcysteine. The reactive metabolite was subsequently identified to be N-acetyl-p-benzoquinone imine (NAPQI). Although covalent binding has been shown to be an excellent correlate of toxicity, a number of other events have been shown to occur and are likely important in the initiation and repair of toxicity. Recent data have shown that nitrated tyrosine residues as well as acetaminophen adducts occur in the necrotic cells following toxic doses of acetaminophen. Nitrotyrosine was postulated to be mediated by peroxynitrite, a reactive nitrogen species formed by the very rapid reaction of superoxide and nitric oxide (NO). Peroxynitrite is normally detoxified by GSH, which is depleted in acetaminophen toxicity. NO synthesis (serum nitrate plus nitrite) was dramatically increased following acetaminophen. In inducible nitric oxide synthase (iNOS) knockout mice, acetaminophen did not increase NO synthesis or tyrosine nitration; however, histological evidence indicated no difference in toxicity. Acetaminophen did not cause hepatic lipid peroxidation in wild-type mice but did cause lipid peroxidation in iNOS knockout mice. These data suggest that NO may play a role in controlling lipid peroxidation and that reactive nitrogen/oxygen species may be important in toxicity. The source of the superoxide has not been identified, but our recent finding that NADPH oxidase knockout mice were equally sensitive to acetaminophen and had equal nitration of tyrosine suggests that the superoxide is not from the activation of Kupffer cells. It was postulated that NAPQI-mediated mitochondrial injury may be the source of the superoxide. In addition, the significance of cytokines and chemokines in the development of toxicity and repair processes has been demonstrated by several recent studies. IL-1β is increased early in acetaminophen toxicity and may be important in iNOS induction. Other cytokines, such as IL-10, macrophage inhibitory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1), appear to be involved in hepatocyte repair and the regulation of proinflammatory cytokines.

Footnotes

↵1 Abbreviations used are: NAPQI, N-acetyl-p-benzoquinone imine; GSH, glutathione; IL, interleukin; TNF-α, tumor necrosis factor-α; NO, nitric oxide; iNOS, inducible nitric oxide synthase; IFN-γ, interferon-γ; MIF, macrophage migration inhibitory factor; MPT, mitochondrial permeability transition.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant 02971 to L.P.J. and National Institute of General Medical Sciences Grant 58884 to J.A.H.
Laura James received her M.D. from the University of South Carolina in 1989. She completed an internship and residence in Pediatrics at University of Arkansas and Arkansas Children's Hospital in 1992. She then completed a fellowship in Pediatric Emergency Medicine at the University of Alabama at Birmingham in 1994, followed by a fellowship in Pediatric Pharmacology/Toxicology at University of Arkansas for Medical Sciences in 1996. She is an Associate Professor in the Department of Pediatrics at the University of Arkansas for Medical Sciences. Her research interests include acetaminophen toxicity and drug metabolism in children. She is a member of the American Academy of Pediatrics, the American Society for Clinical Pharmacology and Therapeutics, The American College of Clinical Toxicology, and Society for Pediatric Research.
Philip Mayeux received his Ph.D. in pharmacology from Tulane University in 1987. After completing postdoctoral fellowships with Dr. Perry V. Halushka at the Medical University of South Carolina and Dr. Sudhir V. Shah at Tulane University, he joined the faculty of the Department of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences. He is an Associate Professor of Pharmacology and Toxicology and directs the Ph.D. program in Pharmacology. His research interests are on the role of reactive nitrogen species in renal and hepatic failure. He is on the editorial board of the Journal of Pharmacology and Experimental Therapeutics and is a member of ASPET, SOT, American Society of Nephrology, and Nitric Oxide Society.
Jack Hinson received a Ph.D. in biochemistry from Vanderbilt University in 1972. Subsequently, he was a postdoctoral fellow and a senior staff fellow in the Laboratory of Chemical Pharmacology at the National Institutes of Health where he worked with Dr. James R. Gillette. In 1980 he transferred to FDA's National Center for Toxicological Research where he was Chief of the Biochemical Mechanisms Branch. In 1990 he assumed his current position of Professor and Director of the Division of Toxicology, Department of Pharmacology and Toxicology at the University of Arkansas for Medical Sciences. He directs a Ph.D. program in Interdisciplinary Toxicology. His research interests are on the role of drug metabolism and reactive oxygen/nitrogen species in drug-induced liver toxicity. He is the editor of Drug Metabolism Reviews and is on the editorial boards of Toxicology and Applied Pharmacology and the Journal of Toxicology and Environmental Health. He serves as a member of a National Institutes of Health advisory panel and is a member of SOT, ASPET, Nitric Oxide Society, and ISSX.
- Received March 20, 2003.
- Accepted June 25, 2003.