TY - JOUR T1 - Relative Contributions of CYP1A2 and CYP2E1 to the Bioactivation and Clearance of 4-Aminobiphenyl in Adult Mice JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 916 LP - 921 DO - 10.1124/dmd.115.063297 VL - 43 IS - 7 AU - Shuang Wang AU - Debbie Bott AU - Aveline Tung AU - Kim S. Sugamori AU - Denis M. Grant Y1 - 2015/07/01 UR - http://dmd.aspetjournals.org/content/43/7/916.abstract N2 - 4-Aminobiphenyl (ABP), a prototypical aromatic amine carcinogen in rodents and humans, requires bioactivation to manifest its toxic effects. A traditional model of ABP bioactivation, based on in vitro enzyme kinetic evidence, had postulated initial N-hydroxylation by the cytochrome P450 isoform CYP1A2. This is followed by phase 2 O-conjugation and hydrolysis to form a reactive nitrenium ion that covalently binds to DNA and produces tumor-initiating mutations. However, Cyp1a2(−/−) mice still possess significant liver ABP N-hydroxylation activity, DNA damage, and incidence of ABP-induced liver tumors, and in vivo induction of CYP1A2 paradoxically reduces levels of ABP-induced DNA damage. Competing ABP detoxification pathways can include N-acetylation by arylamine N-acetyltransferase 1 (NAT1) and/or NAT2; however, wild-type and Nat1/2(−/−) mice have similar in vivo ABP clearance rates. Together, these studies suggest the existence of novel ABP bioactivating and clearance/detoxification enzymes. In the present study, we detected similar reductions in Vmax for ABP N-hydroxylation by liver microsomes from Cyp1a2(−/−) and Cyp2e1(−/−) mice when compared with wild-type mice. In addition, recombinant mouse CYP1A2 and CYP2E1 were both able to N-hydroxylate ABP in mouse hepatoma cells. However, the in vivo clearance of ABP was significantly reduced in Cyp1a2(−/−) but not in Cyp2e1(−/−) mice. Our results support a significant role for CYP2E1 as a novel ABP N-oxidizing enzyme in adult mice, and suggest a more important contribution of CYP1A2 to the in vivo plasma clearance and thus detoxification of ABP. ER -