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ToxSci Advance Access published online on May 28, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg133
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received February 24, 2003; accepted April 24, 2003
© 2003 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 1, Uday S. Devanaboyina 1, Mark A. Doll 1, Shuang Zhao 1, Gong H. Xiao 1, David W. Hein 1*

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

* To whom correspondence should be addressed. E-mail: d.hein{at}louisville.edu.


  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 (4 x 100 mg/kg) or N-hydroxy-PhIP (1 x 50 mg/kg), with 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 (P<0.05) higher in liver, small intestine, and esophagus of rapid than 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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