Acetaminophen metabolism
Acetaminophen metabolism.
Acetaminophen is a widely used analgesic and antipyretic agent considered safeat therapeutic doses. However, it can cause acute hepatic centrilobular necrosis in bothhumans and experimental animals when consumed in large doses.
Acetaminophen is bioactivated by following enzymes: Cytochrome P450, family 1,subfamily A, polypeptide 1 ( CYP1A1 ) [1], Cytochrome P450, family 1,subfamily A, polypeptide 2 ( CYP1A2) [2] [3], CytochromeP450, 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, polypeptide1 (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 by two pathways toform a toxic intermediate N-acetyl-1,4-benzoquinone imine believed to beresponsible for the hepatotoxicity of Acetaminophen, and a nontoxic catecholmetabolite 3-Hydroxy-acetaminophen.
At normal Acetaminophen dosing, N-acetyl-1,4-benzoquinone imine israpidly detoxified by Glutathione S-transferase pi 1 ( GSTP1 ) to nontoxicmetabolite (Acetylamino-2-hydroxyphenyl)-glutathione. Additionally,N-acetyl-1,4-benzoquinone imine can be enzymatically reduced back toAcetaminophen by NAD(P)H dehydrogenase, quinone 1 ( NQO1 ) [10], [11].
Acetaminophen can also be metabolized via an alternative pathway that involvesits sulfation by sulfotransferases, such as Sulfotransferase family, cytosolic, 1A,phenol-preferring, member 1 ( SULT1A1 ) [12], [13], [14]) or glucuronidation by UDP-glucuronosyltransferases, such as UDPglucuronosyltransferase 1 family, polypeptide A1 ( UGT1A1 ) [15],[16], [17], UDP glucuronosyltransferase 1 family, polypeptideA10 ( 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], UDPglucuronosyltransferase 2 family, polypeptide B15 ( UGT2B15 ) [17],[16].
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