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 [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.
Footnotes
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This work was supported by the Department of Veterans Affairs (T.V.Z.) and National Cancer Institute Grant CA72613 (T.V.Z.). Mass spectrometry was performed at Washington University School of Medicine, through National Institutes of Health Grants P41-RR00954, P30 DK56341, and P60-DK20579.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019166.
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ABBREVIATIONS: IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; HCA, heterocyclic amine; P450, cytochrome P450; DSS, dextran sulfate sodium; demethyl-IQ, 2-aminoimidazo[4,5-f]quinoline; SKF-525A, 2-diethylaminoethyl 2:2-diphenylvalerate hydrochloride; DMSO, dimethylsulfoxide; HPLC, high-performance liquid chromatography; N-acetyl-IQ, N-acetyl-2-amino-3-methylimidazo[4,5-f]quinoline; EROD, 7-ethoxyresorufin O-deethylation; ESI, electrospray ionization; MS, mass spectrometry.
- Received October 11, 2007.
- Accepted March 18, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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