Pathway maps

Acetaminophen metabolism
Acetaminophen metabolism

Object List (links open in MetaCore):

GSTP1, CYP2D6, UGT2B15, (Acetylamino-2-hydroxyphenyl)- glutathione, CYP2A13, CYP1A2, UGT1A3, 3-Hydroxy- acetaminophen, NQO1, Acetaminophen O-glucuronide, 1.14.14.1, N-Acetyl-1,4-benzoquinone imine, CYP2E1, Acetaminophen, CYP2A6, CYP3A4, UGT1A6, 1.14.14.1, 2.4.1.17, UGT1A10, CYP2B1 Rat, SULT1A1, 2.8.2.1, CYP1A1, 1.6.5.2, 2.5.1.18, UGT1A9, Acetaminophen sulfate, UGT1A1

Description

Acetaminophen metabolism

Acetaminophen is a widely used analgesic and antipyretic agent considered safe at therapeutic doses. However, it can cause acute hepatic centrilobular necrosis in both humans and experimental animals when consumed in large doses.

Acetaminophen is bioactivated by the enzymes Cytochrome P450, family 1, subfamily A, polypeptide 1 ( CYP1A1 ) [1], Cytochrome P450, family 1, subfamily A, polypeptide 2 ( CYP1A2) [2] [3], Cytochrome P450, family 2, subfamily A, polypeptide 6 ( CYP2A6 ) [4], [5], [3], Cytochrome P450, family 2, subfamily b, polypeptide 1 ( CYP2B1 ) rat [1], Cytochrome P450, family 2, subfamily E, polypeptide 1 (CYP2E1 ) [4], [6], [3], [7], [8], Cytochrome P450, family 3, subfamily A, polypeptide 4 ( CYP3A4 ) [3], Cytochrome P450, family 2, subfamily D, polypeptide 6 ( CYP2D6 ) [5], and cytochrome P450, family 2, subfamily A, polypeptide 13 ( CYP2A13 ) [9]. It is oxidized via two pathways to form a toxic intermediate N-acetyl-1,4-benzoquinone imine believed to be responsible for the hepatotoxicity of Acetaminophen, and a nontoxic catechol metabolite 3-Hydroxy-acetaminophen.

At normal Acetaminophen dosing, N-acetyl-1,4-benzoquinone imine is rapidly detoxified by Glutathione S-transferase pi 1 ( GSTP1 ) to nontoxic metabolite (Acetylamino-2-hydroxyphenyl)-glutathione. Additionally, N-acetyl-1,4-benzoquinone imine can be enzymatically reduced back to Acetaminophen by NAD(P)H dehydrogenase, quinone 1 ( NQO1 ) [10], [11].

Acetaminophen can also be metabolized via an alternative pathway that involves its sulfation by sulfotransferases, such as Sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1 ( SULT1A1 ) [12], [13], [14] ) or glucuronidation by UDP-glucuronosyltransferases, such as UDP glucuronosyltransferase 1 family, polypeptide A1 ( UGT1A1 ) [15], [16], [17], UDP glucuronosyltransferase 1 family, polypeptide A10 ( UGT1A10 ) [15], UDP glucuronosyltransferase 1 family, polypeptide A3 ( UGT1A3 ) [18], UDP glucuronosyltransferase 1 family, polypeptide A6 ( UGT1A6 ) [16], [15], [17], UDP glucuronosyltransferase 1 family, polypeptide A9 ( UGT1A9 ) [15], [16], [19], [17], or UDP glucuronosyltransferase 2 family, polypeptide B15 ( UGT2B15 ) [17], [16].

References:

  1. Myers TG, Thummel KE, Kalhorn TF, Nelson SD
    Preferred orientations in the binding of 4'-hydroxyacetanilide (acetaminophen) to cytochrome P450 1A1 and 2B1 isoforms as determined by 13C- and 15N-NMR relaxation studies. Journal of medicinal chemistry 1994 Mar 18;37(6):860-7
  2. Raucy JL, Lasker JM, Lieber CS, Black M
    Acetaminophen activation by human liver cytochromes P450IIE1 and P450IA2. Archives of biochemistry and biophysics 1989 Jun;271(2):270-83
  3. Hazai E, Vereczkey L, Monostory K
    Reduction of toxic metabolite formation of acetaminophen. Biochemical and biophysical research communications 2002 Mar 8;291(4):1089-94
  4. Chen W, Koenigs LL, Thompson SJ, Peter RM, Rettie AE, Trager WF, Nelson SD
    Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A6. Chemical research in toxicology 1998 Apr;11(4):295-301
  5. Dong H, Haining RL, Thummel KE, Rettie AE, Nelson SD
    Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. Drug metabolism and disposition: the biological fate of chemicals 2000 Dec;28(12):1397-400
  6. Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT
    Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clinical pharmacology and therapeutics 2000 Mar;67(3):275-82
  7. Rowden AK, Norvell J, Eldridge DL, Kirk MA
    Updates on acetaminophen toxicity. The Medical clinics of North America 2005 Nov;89(6):1145-59
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    Acetaminophen poisoning. Clinics in laboratory medicine 2006 Mar;26(1):49-65, viii
  9. Gu J, Zhang QY, Genter MB, Lipinskas TW, Negishi M, Nebert DW, Ding X
    Purification and characterization of heterologously expressed mouse CYP2A5 and CYP2G1: role in metabolic activation of acetaminophen and 2,6-dichlorobenzonitrile in mouse olfactory mucosal microsomes. The Journal of pharmacology and experimental therapeutics 1998 Jun;285(3):1287-95
  10. Aleksunes LM, Goedken M, Manautou JE
    Up-regulation of NAD(P)H quinone oxidoreductase 1 during human liver injury. World journal of gastroenterology : WJG 2006 Mar 28;12(12):1937-40
  11. Moffit JS, Aleksunes LM, Kardas MJ, Slitt AL, Klaassen CD, Manautou JE
    Role of NAD(P)H:quinone oxidoreductase 1 in clofibrate-mediated hepatoprotection from acetaminophen. Toxicology 2007 Feb 12;230(2-3):197-206
  12. Coughtrie MW, Johnston LE
    Interactions between dietary chemicals and human sulfotransferases-molecular mechanisms and clinical significance. Drug metabolism and disposition: the biological fate of chemicals 2001 Apr;29(4 Pt 2):522-8
  13. Coughtrie MW
    Sulfation through the looking glass--recent advances in sulfotransferase research for the curious. The pharmacogenomics journal 2002;2(5):297-308
  14. 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. Molecular pharmacology 2006 Jun;69(6):2084-92
  15. 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. The Journal of pharmacology and experimental therapeutics 2001 Dec;299(3):998-1006
  16. Kostrubsky SE, Sinclair JF, Strom SC, Wood S, Urda E, Stolz DB, Wen YH, Kulkarni S, Mutlib A
    Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes. Toxicological sciences : an official journal of the Society of Toxicology 2005 Sep;87(1):146-55
  17. Mutlib AE, Goosen TC, Bauman JN, Williams JA, Kulkarni S, Kostrubsky S
    Kinetics of acetaminophen glucuronidation by UDP-glucuronosyltransferases 1A1, 1A6, 1A9 and 2B15. Potential implications in acetaminophen-induced hepatotoxicity. Chemical research in toxicology 2006 May;19(5):701-9
  18. Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR
    Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug metabolism and disposition: the biological fate of chemicals 1998 Jun;26(6):507-12
  19. Fujita K, Ando Y, Nagashima F, Yamamoto W, Endo H, Kodama K, Araki K, Miya T, Narabayashi M, Sasaki Y
    Novel single nucleotide polymorphism of UGT1A9 gene in Japanese. Drug metabolism and pharmacokinetics 2006 Feb;21(1):79-81