Acetaminophen-Induced Hepatotoxicity

Abstract

This article is available online at http://dmd.aspetjournals.org 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.

Role of copper,zinc-superoxide dismutase in catalyzing nitrotyrosine formation in murine liver

“…Although the two stimuli APAP and LPS display different chemical properties, metabolic fates, target organs, and abilities to induce NO or peroxynitrite formation [48,49], impacts of SOD1 knockout on their induced hepatic protein nitration remained similar. The inability of either compound to induce strong hepatic protein nitration in the SOD1-/-mice as in the WT indicates a general need for SOD1 to catalyze the process in vivo.…”

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

“…Studies performed with hepatocytes from wild type and PPARβ/δ −/− mice clearly demonstrate that PPARβ/δ plays a pivotal role in ameliorating oxidative stress induced by the hepatoxicant arsenic (Fig. 3C) which originates through free radical reactions and subsequent initiation of lipid peroxidation (reviewed in [11,41]). This data supports our hypothesis that activation of PPARβ/δ by endogenous ligand such as 4-HNE may play a major role in the prevention of pathogenesis of both acute and chronic liver damage.…”

Chemopreventive Efficacy of Moringa oleifera Pods Against 7, 12-Dimethylbenz[a]anthracene Induced Hepatic Carcinogenesis in Mice

“…These enzymes are not normal components of plasma and its function outside organ of origin is unknown (James et al, 2003;Fakurazi et al, 2008). The largest pool of ALT is found in cytosol of hepatic parenchymal cells (Okuda, 1997).…”