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First published on March 20, 2008; DOI: 10.1124/dmd.107.019166

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Received for publication October 16, 2007.
Revised March 18, 2008.
Accepted for publication March 18, 2008.

N-Demethylation is a major route of 2-amino-3-methylimidazo[4,5-f]quinoline metabolism in mouse

Vijaya M. Lakshmi 1, Fong Fu Hsu 2, Terry V. Zenser 1*

1 VA Medical Center-St. Louis University 2 Washington University

* Address correspondence to: E-mail: zensertv{at}slu.edu

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 to 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 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 about 26% of IQ metabolism with the proportion of metabolites the following: 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-amino-imidazo[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 significantly reduced by ellipticine. Liver microsomes only produced Demethyl-IQ. Ellipticine, P450 1A inhibitor, but not furafylline, 1A2 selective inhibitor, prevented microsomal N-demethylation. Inhibitors had similar effects on EROD activity. Demethyl-IQ was not further metabolized by an intact mouse or liver microsomes. Thus, mouse IQ metabolism is significantly different from rat and these differences may affect IQ tumorigenicity. N-Demethylation of IQ-like HCAs occurs in mouse, monkey and human, but not rat.


Key words: carcinogen metabolism, cytochrome P450 catalyzed oxidations, mass spectrometry, metabolite identification


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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.
[Abstract] [Full Text] [PDF]


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