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 i n cynomolgus monkeys. [H-3]PhIP (50 mu mol/kg, p.o) was extensively me tabolized, 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 c onjugate of N-hydroxy-PhIP. All four metabolites were detected in urin e, 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 similar to 64-72% of th e radioactivity excreted. The clearance of PhIP and PhIP metabolites f rom plasma was rapid, with the largest elimination occurring within 8 h. Administration of nine consecutive daily doses of unlabeled PhIP (5 0 mu mol/kg, p.o.) prior to administration of [H-3]PhIP (50 mu mol/kg, p.o.) did not alter the plasma clearance of radiolabeled PhIP or PhIP metabolites, suggesting that this multiple-dose regimen did not induc e or alter PhIP metabolism. PhIP formed DNA adducts in white blood cel ls, as determined by the P-32-postlabeling method. The levels of PhIP- DNA adducts in blood appeared to peak 3 h after administering a single dose of PhIP (50 mu mol/kg, p.o.) and were still detected 1 week afte r dosing. The presence of the glucuronide conjugate of N-hydroxy-PhIP in urine, bile and plasma, and the presence of PhIP-DNA adducts in whi te 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 t hus is a potential carcinogen in this species.