Metabolism of the food-derived mutagen/carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in nonhuman primates

Metabolism of the food-derived heterocyclic amine mutagen/carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) was examined in cynomolgus monkeys. [³H]PhIP (50 μmol/kg, p.o.) was extensively metabolized, with only 1% of the dose excreted into the urine as parent compound. Four metabolites were isolated by HPLC and identified: PhIP-4′-O-glucuronide, PhIP-4′-sulfate, 4′-hydroxy-PhIP and a glucuronide conjugate of N-hydroxy-PhIP. All four metabolites were detected in urine, bile and plasma of monkeys. 4′-Hydroxy-PhIP and PhIP were found in feces. The major PhIP metabolite in urine, bile and plasma was PhIP-4′-sulfate. In urine this metabolite constituted ∼64-72% of the radioactivity excreted. The clearance of PhIP and PhIP metabolites from plasma was rapid, with the largest elimination occurring within 8 h. Administration of nine consecutive daily doses of unlabeled PhIP (50 μmol/kg, p.o.) prior to administration of [³H]PhIP (50 μmol/kg, p.o.) did not alter the plasma clearance of radiolabeled PhIP or PhIP metabolites, suggesting that this multiple-dose regimen did not induce or alter PhIP metabolism. PhIP formed DNA adducts in white blood cells, as determined by the ³²P-postlabeling method. The levels of PhIP-DNA adducts in blood appeared to peak 3 h after administering a single dose of PhIP (50 μmol/kg, p.o.) and were still detected 1 week after dosing. The presence of the glucuronide conjugate of N-hydroxy-PhIP in urine, bile and plasma, and the presence of PnIP-DNA adducts in white blood cells indicate that PhIP undergoes metabolic activation via N-hydroxylation in cynomolgus monkeys. The results suggest that PhIP is activated in vivo to genotoxic metabolites in nonhuman primates and thus is a potential carcinogen in this species.