Acetaminophen hepatotoxicity

Acetaminophen may alter blood glucose test results, causing falsely lower blood glucose values. Use with the barbiturates, hydantoins, isoniazid, and rifampin may increase the toxic effects and possibly decrease the therapeutic effects of acetaminophen. The effects of the loop diuretics may be decreased when administered with acetaminophen. Hepatotoxicity has occurred in chronic alcoholics who are taking moderate doses of acetaminophen. 

Laskin, D. and Pilaro, A. (1986). Potential role of activated macrophages in acetaminophen hepatotoxicity. Toxicol. Appl. Pharmacol. 86, 204-215. 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Oz,H.S. etal. (2004) Diverse antioxidants protect against acetaminophen hepatotoxicity. Journal of Biochemical and Molecular Toxicology, 18 (6), 361-368. 

Bromer MQ, Black M. Acetaminophen hepatotoxicity. Clin Liver Dis. 2003 7 351-367. 

Human CYP2E1 is one of the most efficient P450s to catalyze the oxidation of acetaminophen to NAPQI (157-159). Ethanol and isoniazid cause a time-dependent inhibition and induction of acetaminophen oxidation to NAPQI in humans (160,161) that can decrease risk for hepatotoxicity over the interval of concurrent administration and increase risk for hepatotoxicity a few hours after removal of ethanol or isoniazid. The latter induction phase of CYP2E1 may, in part, be responsible for cases of acetaminophen hepatotoxicity associated with the use of ethanol (162-165) or isoniazid (166-168). However, the induction is modest (2- to 3-fold) therefore, other susceptibility factors, genetic and others such as decreased glutathione stores and nutritional status, are likely to play an important role in some individuals (169-174). 

Kostrubsky SE, Sinclair JF, Strom SC, et al. Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyl transferases in cultured human hepatocytes. Toxicol Sci 2005 87 146-155. 

Nelson SD, Slattery JT, Thummel KE, et al. CAR unlikely to significantly modulate acetaminophen hepatotoxicity in most humans. Hepatology 2003 38 254-257. 

Whitcomb DC, Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. J Am Med Assoc 1994 272 1845-1850. 

Kaplowitz N. Acetaminophen hepatotoxicity what do we know, what don t we know, and what do we do next Hepatology 2004 40 23-26. 

Henderson CJ, Wolf CR, Kitteringham N, Powell H, Otto D, Park BK. Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi. Proc Natl Acad Sci USA 2000 97 12741-5. 

Rumore MM, Blaiklock RG. Influence of age-dependent pharmacokinetics and metabohsm on acetaminophen hepatotoxicity. J Pharm Sci 1992 81(3) 203-7. 

McClain CJ, Kromhout JP, Peterson FJ, Holtzman JL. Potentiation of acetaminophen hepatotoxicity by alcohol. JAMA 1980 244(3) 251-3. 

Licht H, Seeff LB, Zimmerman HJ. Apparent potentiation of acetaminophen hepatotoxicity by alcohol. Ann Intern Med 1980 92(4) 511. 

Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986 104(3) 399 04. 

Holtzman JL. The effect of alcohol on acetaminophen hepatotoxicity. Arch Intern Med 2002 162(10) 1193. 

Brackett CC, Bloch ID. Phenytoin as a possible cause of acetaminophen hepatotoxicity case report and review of the literature. Pharmacotherapy 2000 20(2) 229-33. 

Beyer RP, Fry RC, Lasarev MR, et al. Multicenter study of acetaminophen hepatotox-icity reveals the importance of biological endpoints in genomic analyses. Toxicol Sci. 2007 99(l) 326-337. 

Rumack BH (2002) Acetaminophen hepatotoxicity The first 35 years. Journal of Toxicology. Clinical Toxicology 40 3-20. 

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. 

Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, et al. 2001. High sensitivity of Nr2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol. Sci. 59 169-77... 

DiPetrillo K, Wood S, Kostrubsky V, et al. Effect of caffeine on acetaminophen hepatotoxicity cultured hepatocytes treated with ethanol and isopentanol. Toxicol Appl Pharmacol 2002 185(2) 91 7. 

Acetaminophen is a widely used nonsteroidal, anti-inflammatory agent with hepatotoxic properties.I26l Several studies have shown that pretreatment of laboratory animals with ethanol and isopen-tanol, the predominant alcohols in alcoholic beverages, synergis-tically increases acetaminophen hepatotoxicity. I27 29l... 

Sinclair JF, Szakacs JG, Wood SG, et al. Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with ethanol and isopentanol Protection by triacetyloleandomycin. Biochem Pharmacol 2000 59(4) 445—54. 

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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