Abstract
2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) metabolism was evaluated in mouse to better understand its tumorigenicity. Urinary metabolites from mice orally administered 40 mg/kg [(14)C]IQ were compared with those from similarly treated rats. The recovery of radioactivity was significantly greater in mouse urine. The relative proportion of metabolites was significantly different, and a new rodent metabolite was detected. For rat, the proportion of previously identified metabolites excreted was 5-O-glucuronide > sulfamate > 5-sulfate > N-glucuronide. In mouse urine, a new metabolite, demethyl-IQ, represented approximately 26% of IQ metabolism with the proportion of metabolites as follows: 5-O-glucuronide > demethyl-IQ > sulfamate > N-glucuronide > 5-sulfate. Mouse metabolites were identified by electrospray ionization mass spectrometry. Demethyl-IQ was shown to be 2-aminoimidazo[4,5-f]quinoline. N-Acetyl-2-amino-3-methylimidazo[4,5-f]quinoline was not detected with mice. Mouse liver slices produced 5-O-glucuronide, demethyl-IQ, and sulfamate with the former two being significantly reduced by ellipticine. Liver microsomes only produced demethyl-IQ. Ellipticine, a cytochrome P450 1A inhibitor, but not furafylline, an 1A2 selective inhibitor, prevented microsomal N-demethylation. Inhibitors had similar effects on 7-ethoxyresorufin O-deethylation activity. Demethyl-IQ was not further metabolized by an intact mouse or liver microsomes. Thus, mouse IQ metabolism is significantly different from that in rat, and these differences may affect IQ tumorigenicity. N-Demethylation of IQ-like heterocyclic amines occurs in mouse, monkey, and human but not in rat.