METABOLISM OF THE FOOD-BORNE MUTAGEN 2-AMINO-3,8-DIMETHYLIMIDAZO[4,5-F]QUINOXALINE IN HUMANS

The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx ) was investigated in five human volunteers given a dietary equivalent of C-14-labeled MeIQx. The amount of the dose excreted in urine range d from 20.2% to 58.6%, with unmetabolized MeIQx accounting for 0.7-2.8 % of the dose. Five principal metabolites were detected in urine, and four of the derivatives were characterized by on-line UV spectroscopy and by HPLC-MS following immunoaffinity chromatography. Two metabolite s were identified as the phase II conjugates 3,8-dimethylimidazo[4,5-f ]quinoxalin-2-yl)sulfamic acid (MeIQx-N-2-SO3-) and nyl)-2-amino-3,8-d imethylimidazo[4,5-f]quinoxaline (MeIQx-N-2-Gl). Two other metabolites were the cytochrome P450-mediated (P450) oxidation products 8(hydroxy methyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-MeIQx), and roxy-2- amino-3,8-dimethylimidazo[4,5-f]quinoxaline (NOH-MeIQx-N-2-Gl). The la tter product is a conjugate of the genotoxic metabolite ydroxyamino)-3 ,8-dimethylimidazo[4,5-f]quinoxaline (NHOH-MeIQx). A large interindivi dual variation was observed in the metabolism and disposition of MeIQx ; these four metabolites and unchanged MeIQx combined accounted for 6. 3-26.7% of the total dose. The remaining principal metabolite found in all subjects accounted for 7.6-28% of the dose. It has not been previ ously identified in rodents or nonhuman primates, and its structure re mains unknown. P450-mediated ring oxidation of MeIQx at the C-5 positi on, a major pathway of detoxication in rodents, was not detected in hu mans. Both 8-CH2OH-MeIQx formation and NHOH-MeIQx formation are cataly zed by P450 1A2 and may be useful biomarkers of P450 1A2 activity in h umans. The levels of NHOH-MeIQx-N-2-Gl found in human urine ranged fro m 1.4% to 10.0% of the dose, which is significantly higher than that f ormed in rodents and nonhuman primates undergoing cancer bioassays. Th us, bioactivation of MeIQx by P450-mediated N-oxidation is extensive i n humans.