Hepatotoxicity of acetaminophen

Gardner, C.R. et al., Reduced hepatotoxicity of acetaminophen in mice lacking inducible nitric oxide synthase potential role of tumor necrosis factor-alpha and interleukin-10, Toxicol. Appl. Pharmacol., 184, 27, 2002. 

Laskin, D.L. et al., Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen, Hepatology, 21,1045, 1995. 

The reactions of nucleophiles with benzoquinone and related compounds can also be viewed as Michael reactions. Benzoquinone is one of the reactive metabolites of benzene, a solvent also associated with aplastic anemia (Fig. 8.14). A similar reactive metabolite is responsible for the hepatotoxicity of acetaminophen (Fig. 4.71), the most common cause of acute liver failure however, most of this reactive metabolite is detoxified by reaction with glutathione, and it is only when glutathione is depleted to approximately 10% of the normal level that significant toxicity ensues. 

Fouse BL, Hodgson E. 1987. Effect of chlordecone and mirex on the acute hepatotoxicity of acetaminophen in mice. Gen Pharmacol 18(6) 623-630. 

Johnston SC, Pelletier LL. Enhanced hepatotoxicity of acetaminophen in the alcoholic patient two case reports and a review of the literature. Medicine 1997 ... 

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

Lauterberg BH, Corcoran GB, Mitchell JR. 1983. Mechanism of action of N-acetyl-cysteine in the protection against the hepatotoxicity of acetaminophen in rats in vivo. J. Clin. Invest. 71 990-91... 

The administering of ethanol or acetone prior to administering acetaminophen results in a marked increase in the hepatotoxicity of acetaminophen (because of enzyme induction by ethanol). 14 ... 

Kostrubsky VE, Wood SG, Bush MD, et al. Acute hepatotoxicity of acetaminophen in rats treated with ethanol plus isopentanol. Biochem Pharmacol 1995 50(11) 1743 8. 

The hepatotoxicity of acetaminophen results from the production of the minor metabolite N-acetylbenzoquinone. In small, occasional doses (such as with occasional headache), the drug does not produce significant hepatotoxicity, because this metabolite is produced in only small quantities, and is rapidly inactivated by hepatic-reduced glutathione. However, with frequent or large doses, more of the toxic metabolite is produced, and the reduced glutathione present is not sufficient to inactivate all of the toxic metabolite produced. Thus, toxicity results. 

Gardner CR, Laskin JD, Dambach DM, Chiu H, Durham SK, Zhou P, Bruno M, Gerecke DR, Gordon MK, Laskin DL (2003) Exaggerated hepatotoxicity of acetaminophen in mice lacking tumor necrosis factor receptor-1. Potential role of inflammatory mediators. Toxicol Appl Pharmacol 192 119-130... 

Tolson JK, Dix DJ, Voellmy RW, Roberts SM (2006) Increased hepatotoxicity of acetaminophen in Hsp70i knockout mice. Toxicol Appl Pharmacol 21(X1-2) 157-162 Toumier C, Hess P, Yang DD, Xu J, Turner TK, Nimnual A, Bar-Sagi D, Jones SN, Flavell RA, Davis RJ (2000) Requirement of INK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288(5467) 870-874 Trudell JR, Bosterling B, Trevor AJ (1982) Reductive metabolism of carbrai tetrachlraide by human cytochromes P-450 reconstituted in phospholipid vesicles mass spectral identification of trichloromethyl radical bound to dioleoyl phosphatidylcholine. Proc Natl Acad Sci U S A 79 (8) 2678-2682... 

These data supported the hypothesis that acetaminophen-induced liver toxicity is mediated by covalent binding to critical proteins. In an attempt to further understand the mechanism of hepatotoxicity of acetaminophen, specific proteins to which acetaminophen was covalently bound were isolated and sequenced by our laboratory and by Cohen s laboratory (Cohen et al. 1997). The proteins that were identified by this approach were glutamine synthase, glutamate dehydrogenase,... 

Salas VM, Corcoran GB (1997) Calcium-dependent DNA damage and adenosine 3 5 -cyclic monophosphate- independent glycogen phosphorylase activation in an in vitro model of acetaminophen-induced liver injury. Hepatology 25 1432-1438 Salminen WF Jr, Voellmy R, Roberts SM (1998) Effect of N-acetylcysteine on heat shock protein induction by acetaminophen in mouse liver. J Pharmacol Exp Ther 286 519-524 Schiodt FV, Ott P, Christensen E, Bondesen S (2002) The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther 71 221-225 Schnellmann JG, Pumford NR, Kusewitt DF, Bucci TJ, Hinson JA (1999) Deferoxamine delays the development of the hepatotoxicity of acetaminophen in mice. Toxicol Lett 106 79-88 Shen HM, Pervaiz S (2006) TNF receptor superfamily-induced cell death redox-dependent execution. FASEB J 20 1589-1598... 

Recently, McMurtry et al showed acetaminophen in Fischer rats becomes covalently bound to kidney as well as to liver (34). However, the chemically reactive metabolite in kidney a ears to be produced in the kidney rather than the liver since 3-methylcholanthrene pretreatment increased the covalent binding in the liver but not the kidney. Thus it seemed likely that the chemically reactive metabolite of acetaminophen formed in the liver has too short a half-life to leave the liver to any significant extent. Since N-hydroxyacetaminophen has a relatively long half-life vitro, the possibility that the hepatotoxicity of acetaminophen might be mediated mainly through this metabolite became questionable. 

Immunologic techniques were used to study acetaminophen toxicity in mice to elucidate mechanisms of liver toxicity. The hepatotoxicity of acetaminophen is mediated by a reactive metabolite, N-acetyl-p-ben-zoquinone imine (NAPQI). The metabolite binds to protein as 3-(cystein-S-yl)acetaminophen (3-Cys-A) and the amount of binding correlates with toxicity. This covalent binding, and in particular the 3-Cys-A adduct, is the most reliable biomarker of acetaminophen toxicity (9-12). 

Lee ST, Enters JM, Pineau T, Fernandezsalguero P, Gonzalez FJ. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996 271 12063-12067. 

Acetaminophen is a widely used analgesic. Pretreatment with APAP followed by ethanol intake increases the metabolism of acetaminophen and thereby its toxicity. Binge drinking of ethanol increases the hepatotoxicity of acetaminophen [8]. Caffeine also activates the metabolism of acetaminophen and it, too, increases the hepatotoxicity of acetaminophen. The combination of ethanol and caffeine significantly increases the fiver toxicity of acetaminophen [9]. 

---