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Toxicological Sciences 59, 226-230 (2001)
Copyright © 2001 by the Society of Toxicology

CARCINOGENICITY

Oral Administration of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) Yields PhIP-DNA Adducts but Not Tumors in Male Syrian Hamsters Congenic at the N-acetyltransferase 2 (NAT2) Locus

Adrian J. Fretland*,{dagger},1, Uday S. Devanaboyina*,2, Yi Feng*,{dagger}, Matthew A. Leff*,{dagger}, Gong H. Xiao*, Stephanie J. Webb* and David W. Hein*,{dagger},3

* Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky 40292; and {dagger} Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen present in well-done meat. PhIP must undergo host-mediated bioactivation to exert its mutagenic and carcinogenic effects. Following N-hydroxylation, N-acetyltransferases catalyze the O-acetylation (activation) of N-hydroxy-PhIP to an electrophile causing DNA damage. A well-defined genetic polymorphism in N-acetyltransferase 2 (NAT2) activity exists in humans and the Syrian hamster. Since some human epidemiological studies suggest an association between acetylator genotype and cancer susceptibility in individuals who consume well done meats, this study was designed to investigate the specific role of acetylator genotype in PhIP-induced tumors using a Syrian hamster model congenic at the NAT2 locus. Following oral administration of PhIP to male rapid and slow acetylator Syrian hamsters, DNA adducts were identified in each tissue examined with levels in the relative order: pancreas > heart and urinary bladder > prostate, small intestine and transverse colon > ascending colon, liver, cecum, descending colon, and rectum. However, no tumors were observed in male rapid and slow acetylator congenic hamsters administered 11 oral doses of PhIP (75 mg/kg) and maintained on a high fat diet for one year.

Key Words: N-acetyltransferase 2 (NAT2); 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP; acetylator genotype; DNA adducts; Syrian hamster.


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