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
Acetaminophen is bioactivated by the enzymes Cytochrome
P450, family 1, subfamily A, polypeptide 1 (CYP1A1) , Cytochrome P450, family 1, subfamily A, polypeptide 2
(CYP1A2)  , Cytochrome P450, family 2, subfamily A,
polypeptide 6 (CYP2A6) , , , Cytochrome P450, family 2, subfamily b, polypeptide 1
(CYP2B1) rat , Cytochrome P450, family 2,
subfamily E, polypeptide 1 (CYP2E1) , , , , , Cytochrome P450, family
3, subfamily A, polypeptide 4 (CYP3A4) ,
Cytochrome P450, family 2, subfamily D, polypeptide 6
(CYP2D6) , and cytochrome P450, family 2,
subfamily A, polypeptide 13 (CYP2A13) . 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
Additionally, N-acetyl-1,4-benzoquinone imine can be
enzymatically reduced back to Acetaminophen by NAD(P)H
dehydrogenase, quinone 1 (NQO1) , .
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) , , ) or glucuronidation by UDP-glucuronosyltransferases, such as UDP
glucuronosyltransferase 1 family, polypeptide A1
(UGT1A1) , , , UDP glucuronosyltransferase 1 family, polypeptide A10
(UGT1A10) , UDP glucuronosyltransferase 1
family, polypeptide A3 (UGT1A3) , UDP
glucuronosyltransferase 1 family, polypeptide A6
(UGT1A6) , , , UDP glucuronosyltransferase 1 family, polypeptide A9
(UGT1A9) , , , , or UDP glucuronosyltransferase 2 family, polypeptide
B15 (UGT2B15) , .
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