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 THERAT AS A MODEL FOR HUMAN BIOMONITORING

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 b lood proteins were examined in the rat to develop methods of human bio monitoring. Hemoglobin and serum albumin were among many blood protein s modified. Approximately 0.01% of the dose for both compounds was bou nd to these proteins, and induction of cytochrome P-450 with polychlor obiphenyls resulted in decreased levels of adduction. Hemoglobin sulfi nic 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 pro tein binding. Major routes of detoxification of both contaminants incl uded cytochrome P-450-mediated ring hydroxylation at the C-5 position followed by conjugation to glucuronic or sulfuric acid. Direct conjuga tion to the exocyclic amine group through N-glucuronidation and sulfam ate formation were other important routes of inactivation, but N-acety lation was a minor pathway. The N-glucuronide conjugate of the mutagen ic metabolite N-hydroxy-MeIQx was also detected in urine. Rats given M eIQx at 10 mug/kg excreted 20% of the dose in urine within 24 hr and t he 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 r anging from 0.5 to 3% of the dose, whereas 0.5 to 2% was detected as u nmetabolized MeIQx. Human hepatic microsomes activated IQ and MeIQx by N-hydroxylation, but neither compound was a substrate for hepatic cyt osol N-acetyltransferases. Both IQ and MeIQx were substrates for hepat ic cytosol sulfotransferases, forming the sulfamate derivatives. Immun oaffinity chromatography was used to rapidly purify MeIQx and several metabolites from rat urine as a model for human biomonitoring. Trace l evels of MeIQx were detected in urine of humans within 24 hr of consum ption of cooked meat by analysis with negative ion GC-MS. Analytical m ethods are under development for measuring polar metabolites that may be present in human urine.