Major routes of metabolism of the food-borne carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in the rat.

Abstract

The metabolic fate of 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), a carcinogen formed in cooked meat and fish, has been investigated in male Sprague-Dawley rats. Five metabolites were recovered from bile of animals given an intragastric dose of [2-14C]MeIQx. These accounted for nearly all of the radioactivity in bile. The chemical structures of these metabolites were elucidated by proton NMR, UV and mass spectroscopy. Three structures may be assigned unambiguously: two sulfamates, N-(3,8-dimethylimidazo [4,5-f]quinoxalin-2-yl)sulfamic acid and N-(8-hydroxy-methyl-3-methylimidazo[4,5-f]quinoxalin-2-yl) sulfamic acid, and one glucuronide, N2-(beta-1-glucosiduronyl)-2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline. In addition, an acetyl and a glucosiduronyl conjugate of 5-hydroxy-MeIQx were observed. The spectral evidence did not allow an unambiguous assignment of the site of conjugation. The two glucuronides were excreted in urine and the sulfamate of MeIQx was found in feces as well as urine. All five metabolites were found to be non-mutagenic to Salmonella typhimurium TA98 with or without metabolic activation. The glucuronide conjugates were found also to be non-mutagenic when beta-glucuronidase was incorporated with S-9 mixture in the mutation assay, and thus all appear to be detoxification products. The previously reported metabolite, 2-amino-8-hydroxymethyl-3-methylimidazo[4,5-f]quinoxaline which is mutagenic to Salmonella typhimurium TA98 with metabolic activation, was identified as a minor component in both urine and feces.