title: Reduced 4-aminobiphenyl-induced liver tumorigenicity but not DNA damage in arylamine N-acetyltransferase null mice.
abstract: The aromatic amine 4-aminobiphenyl (ABP) is a liver procarcinogen in mice, requiring enzymatic bioactivation to exert its tumorigenic effect. To assess the role of arylamine N-acetyltransferase (NAT)-dependent acetylation capacity in the risk for ABP-induced liver tumors, we compared 1-year liver tumor incidence following the postnatal exposure of wild-type and NAT-deficient Nat1/2(-/-) mice to ABP. At an ABP exposure of 1200 nmol, male Nat1/2(-/-) mice had a liver tumor incidence of 36% compared to 69% in wild-type males, and at 600 nmol there was a complete absence of tumors compared to 60% in wild-type mice. Only one female wild-type mouse had a tumor using this exposure protocol. However, levels of N-deoxyguanosin-8-yl-ABP-DNA adducts did not correlate with either the strain or sex differences in tumor incidence. These results suggest that female sex and NAT deficiency reduce risk for ABP-induced liver tumors, but by mechanisms unrelated to differences in DNA-damaging events.
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Sugamori
authors.forename: Debbie
authors.initials: D
authors.lastname: Brenneman
authors.forename: Otto
authors.initials: O
authors.lastname: Sanchez
authors.forename: Mark A
authors.initials: MA
authors.lastname: Doll
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
authors.forename: William M
authors.initials: WM
authors.lastname: Pierce
authors.forename: Denis M
authors.initials: DM
authors.lastname: Grant
mesh_terms: D000611:Aminobiphenyl Compounds / Q000633:toxicity*; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D004249:DNA Damage; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D000611:Aminobiphenyl Compounds; D002273:Carcinogens; C006757:4-biphenylamine; D001191:Arylamine N-Acetyltransferase