title: Effect of N-acetyltransferase 2 polymorphism on tumor target tissue DNA adduct levels in rapid and slow acetylator congenic rats administered 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline.
abstract: 2-Amino-3,8-dimethylimidazo-[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are suspected human carcinogens generated in well done meats. After N-hydroxylation, they are O-acetylated by N-acetyltransferase 2 (NAT2) to electrophiles that form DNA adducts. dG-C8-MeIQx and dG-C8-PhIP adducts have been identified in human tissues. In the female rat, administration of PhIP leads to mammary and colon tumors, whereas MeIQx induces liver tumors. Both humans and rats exhibit NAT2 genetic polymorphism yielding rapid and slow acetylator phenotypes. Because O-acetylation is an activation pathway, we hypothesized that MeIQx- and PhIP-induced DNA damage would be greater in tumor target tissues and higher in rapid than slow NAT2 acetylators. Adult female rapid and slow acetylator rats congenic at the Nat2 locus received a single dose of 25 mg/kg MeIQx or 50 mg/kg PhIP by gavage, and tissue DNA was isolated after 24 h. Deoxyribonucleoside adducts were identified and quantified by capillary liquid chromatography-tandem mass spectrometry using isotope dilution methods with deuterated internal standards. Major adducts were those bound to the C8 position of deoxyguanosine. dG-C8-PhIP DNA adducts were highest in colon, lowest in liver and did not significantly differ between rapid and slow acetylator congenic rats in any tissue tested. In contrast, dG-C8-MeIQx adducts were highest in liver and significantly (p < 0.001) higher in rapid acetylator liver than in slow acetylator liver. Our results are consistent with the tumor target specificity of PhIP and MeIQx and with increased susceptibility to MeIQx-induced liver tumors in rapid NAT2 acetylators.
authors: Department of Pharmacology and Toxicology, James Graham Brown Cancer Center and Center for Environmental Genomics and Integrative Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA.
authors: Kristin J
authors: KJ
authors: Metry
authors: Jason R
authors: JR
authors: Neale
authors: Jean
authors: J
authors: Bendaly
authors: Ned B
authors: NB
authors: Smith
authors: William M
authors: WM
authors: Pierce
authors: David W
authors: DW
authors: Hein
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D020296:Animals, Congenic; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D018736:DNA Adducts / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D005260:Female; D018390:Gene Targeting / Q000379:methods; D020022:Genetic Predisposition to Disease; D007093:Imidazoles / Q000378:metabolism / Q000633:toxicity*; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D009153:Mutagens / Q000378:metabolism / Q000633:toxicity; D011110:Polymorphism, Genetic / Q000235:genetics*; D011810:Quinoxalines / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D013997:Time Factors
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D009153:Mutagens; D011810:Quinoxalines; C078255:N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D001191:Arylamine N-Acetyltransferase; C541077:NAT2 protein, rat; D003849:Deoxyguanosine