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

Abstract

Metabolism of 2-amino-3-methylimidazD[4,5-Jlquinoline (IQ) and 2-amino-3-dimethylimidazoll4,5-Jjquinoxaline (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% ofthe dose for both compounds was bound to these proteins, and induction ofcytochrome P450 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% ofthe IQ bound to albumin was characterized as an N2-cysteine(34)sulfinyl-IQ linkage. Human dosimetry ofthese carcinogens through such adducts may prove difficult due to the low kvels of protein binding. Major routes of dfiation of both contaminants included cytochrome P450-mediated ring hydroxylation at the C-S 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 Nglucuronide conjugate of the mutagenic metabolite N-hydroxy-MeIQx was also detected in urine. Rats given MeIQx at 10 jAg/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 05 to 3% of the dose, whereas 0.5 to 2% was detected as unmetabolized MeIQx. Hunan 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 lf te derivatives. Immunoaf18fi chromatography was used torapidly purify MeIQx and sweral metabolites from rat urine as a model for human biomonitoring. Trace levels of MeIQx vere 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.

1 H Nuclear Magnetic Resonance Spectroscopy-Based Studies of the Metabolism of Food-Borne Carcinogen 2-Amino-3-Methylimidazo[4,5- f ]Quinoline by Human Intestinal Microbiota

“…Liver cytochrome P450 in humans and rats is able to realize several hydroxylations of the IQ molecule, but never at position 7 (33). Furthermore, Rumney et al have clearly shown that this metabolite cannot be produced by feces of germfree rats, while it is always produced by feces of conventional or HMA rats (27).…”