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Pharmacology and Metabolism

Acetaminophen (paracetamol, N-acetyl-p-aminophenol, 4-hydroxyacetanilide) is a widely used analgesic and antipyretic. Adverse effects from acetaminophen (APAP) are rare at therapeutic doses of 500-1000 mg three to four times daily (#Koch-Weser, 1976) in humans. Yet even with a high margin of safety, APAP toxicity remains the leading cause of drug-induced liver failure in the United States (#Lee, 2003). Single doses of APAP in humans around 15 g carry a great risk of hepatotoxicity (#Ameer and Greenblatt, 1977), although doses of as little as 6.2 g may result in liver damage (#Bailey, 1980). Overexposure to APAP results in fulminating centrilobular hepatic necrosis, which can bridge to the periportal regions of the liver lobule (#Mitchell et al., 1973a). APAP is primarily metabolized by conjugation with sulfate and glucuronic acid (#Cummings et al., 1967), while a small percentage of the dose undergoes bioactivation by cytochrome P450 enzymes to the reactive intermediate N-acetyl p-benzoquinoneimine (NAPQI) (#Miner and Kissinger, 1979). At non-toxic doses, NAPQI is eliminated from the liver after conjugation with reduced glutathione (GSH) (#Mitchell et al., 1973). However, with toxic doses, the two main conjugation pathways for APAP become saturated, resulting in increased formation of NAPQI. Consequently, detoxification of NAPQI is compromised when existing stores of GSH have been depleted and NAPQI then binds to cellular macromolecules, initiating cell death pathways (#Jollow et al., 1973(#Potter et al., 1974).

Cellular targets for NAPQI include cysteine groups in specific hepatic proteins.  A high degree of correlation exists between arylation of 'APAP binding proteins' and toxicity (#Jollow et al., 1973), leading the authors to conclude that APAP binding may modulate the biological function of vital hepatic macromolecules. The interest in identifying specific APAP binding proteins stems from experiments with 3'-hydroxyacetanilide (HAA), a regioisomer of APAP. HAA covalently binds to proteins, but does not result in toxicity at comparative doses to APAP (#Hinson et al., 1980). These findings suggest that the protein target, rather than random covalent binding may be responsible for toxicity. Generation of multiple antibodies facilitated initial identification of several APAP binding proteins located in the cytosolic, microsomal, and mitochrondrial compartments. Antibody directed identification of APAP binding proteins suggests the most extensive adducts occur to cytosolic liver proteins roughly 56-58kDa in size (#Bartolone et al., 1988)(#Bartolone et al., 1992)(#Pumford et al., 1997). There is a high degree of homology between the 58-kDa APAP binding protein and a hepatic selenium binding protein (#Bartolone et al., 1992). Other cytosolic targets include a 38kDa and 100kDa APAP binding target, glyceraldehyde-3-phosphate dehydrogenase (#Dietze et al., 1997) and N-10-formyltetrahydrofolate dehydrogenase (#Pumford et al., 1997), respectively. Other identified APAP binding targets include glutamine synthetase (#Bulera et al., 1995), aldehyde dehydrogenase (#Landin et al., 1996), lamin-A (#Hong et al., 1994), glutamate dehydrogenase (#Halmes et al., 1996), and carbamyl phosphate synthetase I (#Gupta et al., 1997). With the advent of mass spectrometry based techniques, many additional APAP binding targets were identified (#Qiu et al., 1998). Although arylation of certain proteins can modulate their activity, such as aldehyde dehydrogenase (#Landin et al., 1996) and N-10-formyltetrahydrofolate dehydrogenase (#Pumford et al., 1997), it is unclear how this may affect biological function.

In addition, APAP toxicity increases production of reactive oxygen and nitrogen species, and is often accompanied by lipid peroxidation. This feature of APAP toxicity is shared by other hepatotoxicants (reviewed by #Bessems and Vermeulen, 2001). The oxidative stress component of APAP toxicity is indicated by the profound hepatoprotection afforded by co-administration of a number of antioxidants including ascorbic acid, cysteamine, and a-tocopherol (#Lake et al., 1981) (#Fairhurst et al., 1982). The mechanism responsible for reactive oxygen species production in APAP toxicity remains unresolved. Proposed mechanisms include redox cycling by an APAP metabolite (#Younes et al., 1986) or futile cycling of cytochrome P450s(#Goeptar et al., 1995), generating superoxide anion radicals (O2-.) from the reduction of molecular oxygen. Superoxide is enzymatically reduced to hydrogen peroxide (H2O2), but can also result in hydroxyl radical formation (OH). Hydroxyl radicals can bind to lipids, generating lipid peroxides that may negatively affect biological function. Lipid peroxides have been regarded as an important initiation event in the progression of APAP toxicity (#Wendel et al., 1982) (#Thelen and Wendel, 1983).

Reactive nitrogen species, namely peroxynitrite, are thought to contribute to APAP toxicity (reviewed by #Hinson et al., 2004). Nitrotyrosine residues occur in the centrilobular region of hepatocytes in mice treated with a toxic dose of APAP (#Hinson et al., 1998). Peroxynitrite (ONOO-) is generated by superoxide reacting with nitric oxide, ultimately adducting to tyrosine forming nitrotyrosine. These residues are formed after APAP covalent binding occurs, roughly at the same time that toxicity develops (#Hinson et al., 1998) (#Hinson et al., 2002). Thus, interactions between reactive oxygen and nitrogen species may have important roles in the initiation and progression of APAP toxicity.


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