Abstract
The metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant compound of the aminoimidazoazaarens (AIA) group of mutagens/carcinogens isolated from the crust of fried and broiled meat, was examined in freshly isolated hepatocytes from untreated rat, mouse, hamster, and guinea pig. Activation was evaluated by the total level of covalent binding of PhIP to macromolecules. Rat hepatocytes had the lowest rate of metabolism, both to reactive and detoxified metabolites. The products were identified as 4'-PhIP-sulfate, PhIP-glucuronide, and N(OH)-PhIP-glucuronide. The ring hydroxylation rate was much greater in mouse hepatocytes, the main products being 4'-PhIP-sulfate and 4-hydroxy-PhIP. The level of covalent binding in the mouse hepatocytes exceeded those of the rat and guinea pig at high doses of PhIP. An extensive metabolism was seen in guinea pig hepatocytes, the major products being 4'-PhIP-sulfate, 4'-O-PhIP glucuronide, PhIP-glucuronide, and N(OH)-PhIP-glucuronide. In addition, several other unknown metabolites were formed. However, the amount of covalent binding in guinea pig hepatocytes was similar to that in rat hepatocytes. Covalent binding of PhIP metabolites was highest in hamster hepatocytes. Three of the main metabolites were identified as 4'-PhIP-sulfate, 4'-O-PhIP-glucuronide, and PhIP-glucuronide, but several unknown PhIP metabolites also were formed. Only minor amounts of N(OH)-PhIP-glucuronide were produced in the hamster. The present study shows that both the direct detoxification of PhIP and further conjugation of the 2-hydroxylamino-PhIP to reactive and/or detoxified metabolites are important for the resulting covalent binding.