Xenobiotic Detoxification Pathways: Acetaminophen, Dichloroethylene and Benzo[a]pyrene

Curator(s): Peter D'Adamo

Acetaminophen is bioactivated by the enzymes of the Cytochrome P450 family. 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. Acetaminophen can also be metabolized via an alternative pathway that involves its sulfation by sulfotransferases. Dichloroethylene, a chemical used in the manufacturing of plastics, can cause pulmonary and hepatocellular injury. Mechanism of Dichloroethylene-induced injury involves cytochrome P-450-catalyzed metabolism of this compound resulting in formation of reactive intermediates, such as Dichloroacetaldehyde, Dichloroethylene epoxide, and 2-Chloroacetyl chloride, that bind covalently to bioactive macromolecules in liver. Benzo[a]pyrene is a procarcinogen produced during incomplete combustion of organic compounds such as oil, gasoline and charbroiled food. The mechanism of carcinogenesis of Benzo[a]pyrene is defined by its enzymatic conversion to the ultimate mutagen, Benzo[a]pyrene diol epoxide ( BPDE,). This molecule intercalates in DNA by forming covalent bond with the nucleophilic guanine nucleotide bases at the N2 position. BPDE is the carcinogenic product of three enzymatic reactions.    

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Xenobiotic Detoxification Pathways: Acetaminophen, Dichloroethylene and Benzo[a]pyrene cluster_node66 XENOBIOTIC 1 cluster_node67 XENOBIOTIC 2 cluster_NUCLEUS NUCLEUS cluster_node68 XENOBIOTIC 3 node1 2 UDP glucuronosyltransferase 1 family,polypeptide A3 UGT1A3 UGT1A3->node1 UGT1A3 node18 UGT1A3->node18 node2 3 UDP glucuronosyltransferase 1 family,polypeptide A6 UGT1A6 UGT1A6->node2 UGT1A6 UGT1A6->node18 node60 (3) UGT1A6->node60 node3 4 UDP glucuronosyltransferase 1 family,polypeptide A9 UGT1A9 UGT1A9->node3 UGT1A9 UGT1A9->node18 UGT1A9->node60 node4 3 UDP glucuronosyltransferase 1 family,polypeptide A10 UGT1A10 UGT1A10->node4 UGT1A10 UGT1A10->node18 UGT1A10->node60 node5 4 UDP glucuronosyltransferase 2 family,polypeptide B15 UGT2B15 UGT2B15->node5 UGT2B15 UGT2B15->node18 node6 4 UDP glucuronosyltransferase 1 family,polypeptide A1 UGT1A1 UGT1A1->node6 UGT1A1 UGT1A1->node18 sulfotransferase family,cytosolic,1A,phenol-preferring,member 1 SULT1A1 node17 SULT1A1->node17 cytochrome P450,family 2,subfamily A,polypeptide 13 CYP2A13 node19 (2) CYP2A13->node19 node7 1 cytochrome P450,family 1,subfamily A,polypeptide 1 CYP1A1 CYP1A1->node7 CYP1A1 CYP1A1->node19 node37 (6) CYP1A1->node37 node39 (8) CYP1A1->node39 node40 (9) CYP1A1->node40 node41 (10) CYP1A1->node41 node42 (11) CYP1A1->node42 node53 (12) CYP1A1->node53 cytochrome P450,family 2,subfamily A,polypeptide 6 CYP2A6 node13 (1) CYP2A6->node13 CYP2A6->node19 node8 6 cytochrome P450,family 1,subfamily A,polypeptide 2 CYP1A2 CYP1A2->node8 CYP1A2 CYP1A2->node13 CYP1A2->node19 CYP1A2->node37 node38 (7) CYP1A2->node38 CYP1A2->node40 CYP1A2->node41 node9 5 cytochrome P450,family 2,subfamily E,polypeptide 1 CYP2E1 CYP2E1->node9 CYP2E1 CYP2E1->node13 CYP2E1->node19 node24 (3) CYP2E1->node24 node10 5 glutathione S-transferase pi 1 GSTP1 GSTP1->node10 GSTP1 node15 GSTP1->node15 node44 (6) GSTP1->node44 node46 (7) GSTP1->node46 node11 5 cytochrome P450,family 3,subfamily A,polypeptide 4 CYP3A4 CYP3A4->node11 CYP3A4 CYP3A4->node13 CYP3A4->node37 node12 3 cytochrome P450,family 2,subfamily D,polypeptide 6 CYP2D6 CYP2D6->node12 CYP2D6 CYP2D6->node13 node22 N-acetyl -1,4-benzoquinone imine node13->node22 node14 4 node15->node14 node23 Acetylamino -2 -hydroxyphenyl-glutathione node15->node23 node16 Acetaminophen node16->Acetaminophen Acetaminophen sulphate node17->Acetaminophen sulphate node20 Acetaminophen O-glucuronide node18->node20 node21 3-Hydroxy acetaminophen node19->node21 node22->node15 NAD(P)H dehydrogenase,quinone 1 NQO1 NQO1->node16 Dichloroacetaldehyde node24->Dichloroacetaldehyde node25 (4) Dichloroethylene epoxide node25->Dichloroethylene epoxide node26 (5) node32 2-Chloroacetyl chloride node26->node32 node27 (2) node31 S-(2,2 -Dichloro-1 - hydroxy)ethyl glutathione node27->node31 node28 (3) node33 2-(S -Glutathionyl)acetyl chloride node28->node33 node29 (4) node35 S-(2 -Chloroacetyl)glutathione node29->node35 node30 (5) node34 2-(S -Glutathionyl) acetyl glutathione node30->node34 cytochrome P450,family 2,subfamily F,polypeptide 1 CYP2F1 CYP2F1->node24 glutathione S-transferase alpha 2 GSTA2 GSTA2->node27 GSTA2->node28 GSTA2->node29 GSTA2->node30 Dichloroethylene epoxide->node28 Dichloroacetaldehyde->node27 node32->node29 node33->node30 node50 Benzo[a]pyrene -4,5 -oxide node38->node50 node54 Benzo[a]pyrene - 7,8 -oxide node39->node54 node58 Benzo[a]pyrene -9,10 -oxide node40->node58 node40->node58 node56 Benzo[a]pyrene -diol -epoxide node42->node56 node43 4 node44->node43 (6) node52 4,5 -Dihydro - 4-hydroxy -5-S - glutathionyl- benzo[a]pyrene node44->node52 node45 4 node46->node45 (7) node51 7,8 -Dihydro - 7-hydroxy -8-S - glutathionyl- benzo[a]pyrene node46->node51 node47 (2) node62 12-Hydroxy -benzo[a]pyrene beta-D -glucuronoside node47->node62 node48 node55 Benzo[a]pyrene -7,8 -diol node48->node55 cytochrome P450,family 1,subfamily B,polypeptide 1 CYP1B1 CYP1B1->node37 CYP1B1->node38 CYP1B1->node39 CYP1B1->node42 CYP1B1->node53 cytochrome P450,family 2,subfamily C,polypeptide 18 CYP2C18 CYP2C18->node37 cytochrome P450,family 2,subfamily C,polypeptide 8 CYP2C8 CYP2C8->node37 cytochrome P450,family 2,subfamily C,polypeptide 9 CYP2C9 CYP2C9->node37 node49 3-hydroxy -benzo[a]pyrene node49->node37 node50->node44 node57 9-Hydroxybenzo[a]pyrene -4,5-oxide node53->node57 HYEP HYEP->node48 node54->node48 node55->node42 node55->node46 DNA node56->DNA Covalent modification node57->DNA Covalent modification node58->node57 node59 9-Hydroxy -benzo[a]pyrene node58->node59 node59->DNA Covalent modification node63 11-Hydroxy -benzo[a]pyrene beta-D -glucuronoside node60->node63 node61 12-Hydroxy -benzo[a]pyrene node61->node47 node64 11-Hydroxybenzo(a)pyrene node64->node60 node65 16 Glutathione Glutathione->node15 Glutathione->node27 Glutathione->node28 Glutathione->node29 Glutathione->node30 Glutathione->node44 Glutathione->node46 Glutathione->node65 Glutathione Acetaminophen->node13 Acetaminophen->node17 Acetaminophen->node18 Acetaminophen->node19 node36 Benzo[a]pyrene node36->CYP1A1 node36->CYP1A2 node36->node37 node36->node38 node36->node39 node36->node40 node36->node41 node36->CYP1B1 Dichloroethylene Dichloroethylene->node25 HNF1 homeobox A HNF1A HNF1A->CYP2E1 HNF1A->GSTA2 hepatocyte nuclear factor 4,alpha HNF4A HNF1A->HNF4A HNF4A->HNF1A NRSF NRSF->CYP2E1 Sp1 transcription factor SP1 NRSF->SP1 SP1->HNF4A transcription factor CP2 TFCP2 TFCP2->CYP2F1 TFCP2->NRSF print "