Metabolism of the food-borne carcinogens 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]-quinoxaline in the rat as a model for human biomonitoring

R. J. Turesky, W. G.S. Stillwell, P. L. Skipper, S. R. Tannenbaum

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Metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazol[4,5-f]quinoxaline (MeIQx) and their binding to blood proteins were examined in the rat to develop methods of human biomonitoring. Hemoglobin and serum albumin were among many blood proteins modified. Approximately 0.01% of the dose for both compounds was bound to these proteins, and induction of cytochrome P-450 with polychlorobiphenyls resulted in decreased levels of adduction. Hemoglobin sulfinic acid amide adducts could not be detected for either amine, however, as much as 10% of the IQ bound to albumin was characterized as an N2-cysteine(34)sulfinyl-IQ linkage. Human dosimetry of these carcinogens through such adducts may prove difficult due to the low levels of protein binding. Major routes of detoxification of both contaminants included cytochrome P450-mediated ring hydroxylation at the C-5 position followed by conjugation to glucuronic or sulfuric acid. Direct conjugation to the exocyclic amine group through N-glucuronidation and sulfamate formation were other important routes of inactivation, but N-acetylation was a minor pathway. The N-glucuronide conjugate of the mutagenic metabolite N-hydroxy-MeIQx was also detected in urine. Rats given MeIQx at 10 μg/kg excreted 20% of the dose in urine within 24 hr and the remainder was recovered in feces. The N2-glucuronide was the major metabolite found in urine and accounted for 4% of the total dose. The other metabolites cited above also were excreted in urine at amounts ranging from 0.5 to 3% of the dose, whereas 0.5 to 2% was detected as unmetabolized MeIQx. Human hepatic microsomes activated IQ and MeIQx by N-hydroxylation, but neither compound was a substrate for hepatic cytosol N-acetyltransferases. Both IQ and MeIQx were substrates for hepatic cytosol sulfotransferases, forming the sulfamate derivatives. Immunoaffinity chromatography was used to rapidly purify MeIQx and several metabolites from rat urine as a model for human biomonitoring. Trace levels of MeIQx were detected in urine of humans within 24 hr of consumption of cooked meat by analysis with negative ion GC-MS. Analytical methods are under development for measuring polar metabolites that may be present in human urine.

Original languageEnglish (US)
Pages (from-to)123-128
Number of pages6
JournalEnvironmental health perspectives
StatePublished - Jul 2 1993


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