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Drug Metabolism and Disposition Fast Forward
First published on March 20, 2008; DOI: 10.1124/dmd.107.019166

0090-9556/08/3606-1143-1152$20.00
DMD 36:1143-1152, 2008

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N-Demethylation Is a Major Route of 2-Amino-3-Methylimidazo[4,5-f]quinoline Metabolism in Mouse

Vijaya M. Lakshmi, Fong Fu Hsu, and Terry V. Zenser

VA Medical Center, St. Louis, Missouri (V.M.L., T.V.Z.); Division of Geriatric Medicine (V.M.L., T.V.Z.) and Department of Biochemistry and Molecular Biology (T.V.Z.), St. Louis University School of Medicine, St. Louis, Missouri; and Department of Medicine, Washington University, St. Louis, Missouri (F.F.H.)

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 [14C]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.

Address correspondence to: Dr. Terry V. Zenser, VA Medical Center (11G-JB), St. Louis, MO 63125. E-mail: zensertv{at}slu.edu




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V. M. Lakshmi, F.-F. Hsu, and T. V. Zenser
Identification of New 2-Amino-3-methylimidazo[4,5-f]quinoline Urinary Metabolites from {beta}-Naphthoflavone-Treated Mice
Drug Metab. Dispos., August 1, 2009; 37(8): 1690 - 1697.
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