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 carcinog en 2-amino-3,8-dimethylimidazo[4,5 f]quinoxaline was investigated in c ynomolgus monkeys. Monkeys were administered a single dose of radiolab eled [C-14]MeIQx (2.2 or 50 mu mol/kg). Peak blood levels of radioacti vity were observed within 1-3 h after dosing and declined rapidly ther eafter. 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. Eigh t metabolites and the parent compound were detected in urine by HPLC. The parent compound accounted for similar to 15-25% of the dose excret ed in the urine, Seven MeIQx urinary metabolites were identified. Five metabolites were identical to MeIQx metabolites previously found in r ats: MeIQx-N-2-glucuronide, MeIQx-N-2-sulfamate, MeIQx-5-sulfate, MeIQ x-5-O-glucuronide, and 8-CH2OH-MeIQx-5-sulfate. Cynomolgus monkeys, ho wever, 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-glucuronid e 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 previous ly in any other animal model, was 7-oxo-MeIQx, a likely enteric bacter ial 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 hydroxyamino-3, 8-dimethylimidazo[4,5-f]quinoxaline (NHOH-MeIQx) was not detected in u rine or bile of monkeys, even after 10 daily doses of MeIQx (100 mu mo l/kg) were given. The results indicate that MeIQx is metabolically pro cessed in monkeys via multiple pathways of detoxification. However, Me IQx is poorly metabolically activated via cytochrome P450 mediated N-o xidation. The in vivo metabolism of MeIQx in cynomolgus monkeys is dif ferent from that of the structurally related food-derived mutagen 2-am ino-3 -methylimidazo [4,5-f]quinoline (IQ), which is readily metabolic ally activated by this species and in contrast to MeIQx, has been show n to be a powerful hepatic carcinogen.