Metabolic activation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Syrian hamsters congenic at the N-acetyltransferase 2 (NAT2) locus

Toxicological Sciences : an Official Journal of the Society of Toxicology
Adrian J FretlandDavid W Hein

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 co...Continue Reading

References

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Citations

Nov 1, 2011·Chemistry : a European Journal·Haifeng HuangMin Xue
Nov 21, 2007·Cell Biochemistry and Function·Lokman AyazLülüfer Tamer
Jul 4, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·K S SugamoriD M Grant
Jan 7, 2022·Chemical Research in Toxicology·Tauqeerunnisa Syeda, Jason R Cannon

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