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Glutathione Articles - Acetaminophen Toxicity
Acetaminophen-Induced Hepatotoxicity
Laura P. James, Philip R. Mayeux and Jack A. Hinson
Drug Metabolism and Disposition. 2003;31:1499-1506.
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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-1 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.
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