Acetaminophen covalent binding

Corcoran GB, Racz WJ, Smith CV, Mitchell JR. 1985. Effects of N-acetylcy-steine on acetaminophen covalent binding and hepatic necrosis in mice. J. Pharmacol. Exp. Ther. 232 864—72... 

Bartolone, J. B. Birge, R. B. Sparks, K. Cohen, S. D. Khairallah, E. A. Immunochranical andysis of acetaminophen Covalent binding to proteins partial characterization of the major acetaminophen-binding liver proteins. Biochem. Pharmacol., 37 4763-74. 1988. 

Roberts, S.A., Veronica, F.P. and Jollow, D.J. (1990) Acetaminophen structure-toxicity studies In vitro covalent binding of a non-hepatotoxic analog, 3-hydroxy-acetanilide. Toxicology and Applied Pharmacology, 105, 195-208. 

Damsten, M.C., Commandeur, J.N.M., Fidder, A., Hulst, A.G.,Touw, D., Noort, D. and Vermeulen, N.P.E. (2007) Liquid chromatography/tandem mass spectrometry detection of covalent binding of acetaminophen to human serum albumin. Drug Metabolism and Disposition The Biological Fate of Chemicals, 35 (8), 1408-1417. 

Jollow, D.J. et al. (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. Journal of Pharmacology and Experimental Therapeutics, 187 (1), 195-202. 

Potter WZ, Thorgeirsson SS, JoIIow DJ, et al. Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters. Pharmacology 1974 12 (3) 129-143. 

Gibson FD, Pumford NR, Samokyszyn VM, et al. Mechanism of acetaminophen-induced hepa to toxicity Covalent binding versus oxidative stress. Chem Res Toxicol 1996 9 580. 

Halmes NC, Hinson JA, Martin BM, et al. Glutamate dehydrogenase covalently binds to a reactive metabolite of acetaminophen. Chem Res Toxicol 1996 9 541. 

Treatment of animals with A-acetylcysteine, a precursor of glutathione, protects animals against acetaminophen-induced hepatic necrosis, possibly by reducing covalent binding to tissue macromolecules. However, depletion of glutathione potentiates covalent binding and hepatotoxicity. 

Holtzman JL. The role of covalent binding to microsomal proteins in the hepatotoxicity of acetaminophen. Drug Metab Rev 1995 27 277-97. 

McMurtry RJ, Snodgrass WR, Mitchell JR. Renal necrosis, glutathione depletion, and covalent binding after acetaminophen. Toxicol Appl Pharmacol 1978 46 87-100. 

Mudge GH, Gemborys MW, Duggin GG. Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione. J Pharmacol ExpTher 1978 206 218-226. 

Potter WZ, Davis DC, Mitchell JR, et al. Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-mediated covalent binding in vitro. / Pharmacol Exp Ther. 1973 187(1) 203-210. 

The mechanism of acute acetaminophen nephrotoxicity is related to the bioactivation of acetaminophen and/or its metabolites to highly reactive species which are capable of arylating renal macromolecules or generating reactive oxygen species. Acetaminophen hepatotoxicity is the result of conversion of acetaminophen to the reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI), which can covalently bind to hepatic macromolecules. It is less clear what role formation of NAPQI in the kidney plays in acetaminophen nephrotoxicity. In some species (e.g., the Fischer 344 rat) deacetylation appears to be an important biotransformation step in acetaminophen nephrotoxicity, while in other species (e.g., the CD-I mouse), bioactivation does not appear to require deacetylation of acetaminophen before the ultimate nephrotoxicant species is produced. Therefore, the role of NAPQI in acute acetaminophen nephrotoxicity might be species dependent. 

Numerous studies have demonstrated an apparent relationship between metabolite formation and toxicity. The N-hydroxylation of phenacetin may play a role in drug-induced hepatic necrosis . Similarly, N-hydroxylation may mediate acetaminophen hepatotoxicity . Acetylhydrazine and isopropylhydrazine, metabolites of isoniazid and iproniazid, may initiate hepatotoxicity through covalent binding of an electrophilic intermediate (see Chapter 32) . 

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