Journal Article

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

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

in Toxicological Sciences

Volume 74, issue 2, pages 253-259
Published in print August 2003 | ISSN: 1096-6080
Published online August 2003 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfg133
Metabolic Activation of 2-Hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Syrian Hamsters Congenic at the N-Acetyltransferase 2 (NAT2) Locus

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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 × 100 mg/kg) or N-hydroxy-PhIP (1 × 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.

Keywords: 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

Journal Article.  5127 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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