title: Metabolic activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Syrian hamsters congenic at the N-acetyltransferase 2 (NAT2) locus.
abstract: 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen prevalent in the human diet. To exert its mutagenic and carcinogenic effects, PhIP undergoes bioactivation to N-hydroxy-PhIP followed by O-esterification via cytosolic acetyltransferases or sulfotransferases to form DNA adducts. We investigated the role of cytosolic acetyltransferases and sulfotransferases and the role of the N-acetyltransferase 2 genetic polymorphism on PhIP DNA-adduct levels in a congenic Syrian hamster model. DNA adduct levels were detected in all hepatic and extrahepatic tissues tested following administration of PhIP (4x100 mg/kg) or N-hydroxy-PhIP (1x50 mg/kg), with the highest levels in pancreas. DNA-adduct levels were higher in the gastrointestinal tract of rapid and slow acetylator hamsters administered N-hydroxy-PhIP. N-hydroxy-PhIP O-acetyltransferase and O-sulfotransferase activities were detected in most hepatic and extrahepatic cytosols derived from rapid and slow acetylator congenic hamsters. N-hydroxy-PhIP O-acetyltransferase activity was significantly higher (p<0.05) in liver, small intestine, and esophagus in rapid than in slow acetylator congenic hamsters. N-hydroxy-PhIP O-acetyltransferase activities correlated significantly with N-acetyltransferase 2 activities across tissues in rapid (r=0.83; p=0.0004) but not in slow (r=0.46; p=0.1142) acetylator congenic hamsters, suggesting catalysis primarily by NAT2 in rapid acetylators but NAT1 in slow acetylators. N-hydroxy-PhIP O-sulfotransferase activities did not vary with acetylator genotype. DNA-adduct levels following administration of PhIP or N-hydroxy-PhIP did not correlate with either N-hydroxy-PhIP O-acetyltransferase or O-sulfotransferase catalytic activities.
authors.affiliation: Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fretland
authors.forename: Uday S
authors.initials: US
authors.lastname: Devanaboyina
authors.forename: Mark A
authors.initials: MA
authors.lastname: Doll
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhao
authors.forename: Gong H
authors.initials: GH
authors.lastname: Xiao
authors.forename: David W
authors.initials: DW
authors.lastname: Hein
mesh_terms: D000107:Acetylation; D000818:Animals; D020296:Animals, Congenic; D001191:Arylamine N-Acetyltransferase / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics* / Q000633:toxicity; D006224:Cricetinae; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis / Q000187:drug effects; D005838:Genotype; D007093:Imidazoles / Q000493:pharmacokinetics* / Q000633:toxicity; D008297:Male; D008647:Mesocricetus; D011110:Polymorphism, Genetic; D011725:Pyridines / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D011725:Pyridines; C060533:2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D004247:DNA; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human