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Pathway Description
Acetaminophen Metabolism Pathway
Homo sapiens
Drug Metabolism Pathway
Acetaminophen (APAP) is metabolized primarily in the liver. Glucuronidation is the main route, accounting for 45-55% of APAP metabolism, and is mediatied by UGT1A1, UGT1A6, UGT1A9, UGT2B15 in the liver and UGT1A10 in the gut. APAP can also by metabolized via sulfation, accounting for 30-35% of the metabolism. In the liver, this step is catalyzed by the sulfotransferases SULT1A1, SULT1A3, SULT1A4, SULT1E1 and SULT2A1. Moreover, APAP can also be activated to form the toxic N-acetyl-p-benzoquinone imine (NAPQI) under the mediation of CYP3A4, CYP2E1, CYP2D6 CYP1A2, CYP2E1 and CYP2A6.
References
Acetaminophen Pathway References
[PharmgKB](http://www.pharmgkb.org/pathway/PA165986279)
Bessems JG, Vermeulen NP: Paracetamol (acetaminophen)-induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit Rev Toxicol. 2001 Jan;31(1):55-138. doi: 10.1080/20014091111677 .
Pubmed: 11215692
Adjei AA, Gaedigk A, Simon SD, Weinshilboum RM, Leeder JS: Interindividual variability in acetaminophen sulfation by human fetal liver: implications for pharmacogenetic investigations of drug-induced birth defects. Birth Defects Res A Clin Mol Teratol. 2008 Mar;82(3):155-65. doi: 10.1002/bdra.20535.
Pubmed: 18232020
Bock KW, Forster A, Gschaidmeier H, Bruck M, Munzel P, Schareck W, Fournel-Gigleux S, Burchell B: Paracetamol glucuronidation by recombinant rat and human phenol UDP-glucuronosyltransferases. Biochem Pharmacol. 1993 May 5;45(9):1809-14.
Pubmed: 8494539
Court MH, Duan SX, von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO, Mackenzie PI: Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther. 2001 Dec;299(3):998-1006.
Pubmed: 11714888
Navarro SL, Chen Y, Li L, Li SS, Chang JL, Schwarz Y, King IB, Potter JD, Bigler J, Lampe JW: UGT1A6 and UGT2B15 polymorphisms and acetaminophen conjugation in response to a randomized, controlled diet of select fruits and vegetables. Drug Metab Dispos. 2011 Sep;39(9):1650-7. doi: 10.1124/dmd.111.039149. Epub 2011 Jun 10.
Pubmed: 21666065
Kiang TK, Ensom MH, Chang TK: UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther. 2005 Apr;106(1):97-132. doi: 10.1016/j.pharmthera.2004.10.013. Epub 2005 Jan 12.
Pubmed: 15781124
Nagar S, Walther S, Blanchard RL: Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation. Mol Pharmacol. 2006 Jun;69(6):2084-92. doi: 10.1124/mol.105.019240. Epub 2006 Mar 3.
Pubmed: 16517757
Coughtrie MW: Sulfation through the looking glass--recent advances in sulfotransferase research for the curious. Pharmacogenomics J. 2002;2(5):297-308. doi: 10.1038/sj.tpj.6500117.
Pubmed: 12439736
Bonham Carter SM, Rein G, Glover V, Sandler M, Caldwell J: Human platelet phenolsulphotransferase M and P: substrate specificities and correlation with in vivo sulphoconjugation of paracetamol and salicylamide. Br J Clin Pharmacol. 1983 Mar;15(3):323-30.
Pubmed: 6573904
Laine JE, Auriola S, Pasanen M, Juvonen RO: Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica. 2009 Jan;39(1):11-21. doi: 10.1080/00498250802512830 .
Pubmed: 19219744
Hazai E, Vereczkey L, Monostory K: Reduction of toxic metabolite formation of acetaminophen. Biochem Biophys Res Commun. 2002 Mar 8;291(4):1089-94. doi: 10.1006/bbrc.2002.6541.
Pubmed: 11866476
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