Relative Contributions of CYP1A2 and CYP2E1 to the Bioactivation and Clearance of 4-Aminobiphenyl in Adult Mice.

Abstract

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.

• Authors: Shuang Wang, Debbie Bott, Aveline Tung, Kim S Sugamori, Denis M Grant
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 43 Issue 7 Pg. 916-21 (Jul 2015) ISSN: 1521-009X [Electronic] United States
• PMID: 25922528 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Aminobiphenyl Compounds
• Isoenzymes
• 4-biphenylamine
• Cytochrome P-450 CYP2E1
• Cytochrome P-450 CYP1A2
• Arylamine N-Acetyltransferase
• N-acetyltransferase 1
• Nat2 enzyme, mouse

Topics

• Acetylation
• Activation, Metabolic (genetics)
• Aminobiphenyl Compounds (metabolism, pharmacokinetics)
• Animals
• Arylamine N-Acetyltransferase (genetics, metabolism)
• Cell Line, Tumor
• Cytochrome P-450 CYP1A2 (genetics, metabolism)
• Cytochrome P-450 CYP2E1 (genetics, metabolism)
• DNA Damage
• Hydroxylation
• Isoenzymes (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microsomes, Liver (enzymology)