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ToxSci Advance Access originally published online on May 28, 2003
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Toxicological Sciences 74, 253-259 (2003)
Copyright © 2003 by the Society of Toxicology

BIOTRANSFORMATION AND TOXICOKINETICS

Metabolic Activation of 2-Hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Syrian Hamsters Congenic at the N-Acetyltransferase 2 (NAT2) Locus

Adrian J. Fretland, Uday S. Devanaboyina, Mark A. Doll, Shuang Zhao, Gong H. Xiao and David W. Hein1

Department of Pharmacology and Toxicology and James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, Kentucky 40292

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 (4 x 100 mg/kg) or N-hydroxy-PhIP (1 x 50 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.

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


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