METABOLISM OF THE FOOD-DERIVED CARCINOGEN 2-AMINO-3,8-DIMETHYLIMIDAZO[4,5-F]QUINOXALINE (MEIQX) IN NONHUMAN-PRIMATES

The metabolism and disposition of the food mutagen and rodent carcinogen 2-amino-3,8-dimethylimidazo[4,5 f]quinoxaline was investigated in cynomolgus monkeys. Monkeys were administered a single dose of radiolabeled [C-14]MeIQx (2.2 or 50 mu mol/kg). Peak blood levels of radioactivity were observed within 1-3 h after dosing and declined rapidly thereafter. By 72 h after dosing, approximately 50% and 70% of the 2.2 mu mol/kg, and 50 mu mol/kg dose, respectively, was excreted in the urine. Approximately 15-20% of either dose was recovered in the feces. Eight metabolites and the parent compound were detected in urine by HPLC. The parent compound accounted for similar to 15-25% of the dose excreted in the urine, Seven MeIQx urinary metabolites were identified. Five metabolites were identical to MeIQx metabolites previously found in rats: MeIQx-N-2-glucuronide, MeIQx-N-2-sulfamate, MeIQx-5-sulfate, MeIQx-5-O-glucuronide, and 8-CH2OH-MeIQx-5-sulfate. Cynomolgus monkeys, however, metabolized MeIQx to a novel glucuronide conjugate of MeIQx not found in rats. Based upon mass spectroscopy and proton NMR analyses, the structure of this metabolite was consistent with an N-1-glucuronide of MeIQx. This metabolite was the major urinary metabolite found in monkeys, accounting for 31-37% of the dose excreted in the urine over a 24 h period. One additional metabolite identified in urine and feces of MeIQx treated cynomolgus monkeys, that has not been found previously in any other animal model, was 7-oxo-MeIQx, a likely enteric bacterial metabolite of MeIQx, 7-Oxo-MeIQx accounted for 20-25% of the dose of MeIQx found in the urine and was the major fecal metabolite. The N-2-glucuronide conjugate of the carcinogenic metabolite 2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxaline (NHOH-MeIQx) was not detected in urine or bile of monkeys, even after 10 daily doses of MeIQx (100 mu mol/kg) were given. The results indicate that MeIQx is metabolically processed in monkeys via multiple pathways of detoxification. However, MeIQx is poorly metabolically activated via cytochrome P450 mediated N-oxidation. The in vivo metabolism of MeIQx in cynomolgus monkeys is different from that of the structurally related food-derived mutagen 2-amino-3 -methylimidazo [4,5-f]quinoline (IQ), which is readily metabolically activated by this species and in contrast to MeIQx, has been shown to be a powerful hepatic carcinogen.