Metabolism of the food-derived carcinogen 2-amino-3,8-dimethylimidazo[4,5,-f)quinoxaline (MeIQx) in nonhuman primates

Elizabeth G. Snyderwine, Dieter H. Welti, Cindy D. Davis, Laurent B. Fay, Robert J. Turesky

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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 [14C]MeIQx (2.2 or 50 μmol/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 μmol/kg, and 50 μmol/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 ∼15-25% of the dose excreted in the urine. Seven MelQx urinary metabolites were identified. Five metabolites were identical to MelQx metabolites previously found in rats: MeIQx-N2-glucuronide, MeIQx-N2-sulfamate, MeIQx-5-sulfate, MeIQx-5-O-glucuronide, and 8-CH2OH-MeIQx-5-sulfate. Cynomolgus monkeys, however, metabolized MelQx to a novel glucuronide conjugate of MelQx not found in rats. Based upon mass spectroscopy and proton NMR analyses, the structure of this metabolite was consistent with an N1-glucuronide of MelQx. 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 MelQx treated cynomolgus monkeys, that has not been found previously in any other animal model, was 7-oxo-MeIQx, a likely enteric bacterial metabolite of MelQx. 7-Oxo-MeIQx accounted for 20-25% of the dose of MelQx found in the urine and was the major fecal metabolite. The N2-glucuronide conjugate of the carcinogenic metabo-lite 2-hydroxyamino-3,8-dimethylimidazo[4,5-f]quinoxa-line (NHOH-MelQx) was not detected in urine or bile of monkeys, even after 10 daily doses of MelQx (100 (μmol/kg) were given. The results indicate that MelQx is metabolically processed in monkeys via multiple pathways of detoxification. However, MelQx is poorly metabolically activated via cytochrome P450 mediated N-oxidation. The in vivo metabolism of MelQx in cynomolgus monkeys is different from that of the structurally related food-derived mutagen 2-amino-3-methyllmidazo[4,5-f]quinoline (IQ), which is readily metabolically activated by this species and in contrast to MelQx, has been shown to be a powerful hepatic carcinogen.

Original languageEnglish (US)
Pages (from-to)1377-1384
Number of pages8
Issue number6
StatePublished - Jun 1995


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