Metabolism of the food-borne mutagen 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline in humans

Robert J. Turesky, R. Colin Garner, Dieter H. Welti, Janique Richoz, Steve H. Leveson, Karen H. Dingley, Ken W Turteltaub, Laurent B. Fay

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62 Scopus citations

Abstract

The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was investigated in five human volunteers given a dietary equivalent of 14C-labeled MeIQx. The amount of the dose excreted in urine ranged from 20.2% to 58.6%, with unmetabolized MeIQx accounting for 0.7-2.8% of the dose. Five principal metabolites were detected in urine, and four of the derivatives were characterized by on-line UV spectroscopy and by HPLC-MS following immunoaffinity chromatography. Two metabolites were identified as the phase II conjugates N2,(3,8-dimethylimidazo[4,5-f]quinoxalin-2- yl)sulfamic acid (MeIQx-N2-SO3-) and N2-(β-1-glucosiduronyl)-2-amino- 3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx-N2-Gl). Two other metabolites were the cytochrome P450-mediated (P450) oxidation products 2-amino-8- (hydroxymethyl)-3-methylimidazo[4,5-f]quinoxaline (8-CH2OH-MeIQx), and N2- (β-1-glucosi duronyl)-N-hydroxy-2-amino-3,8-dimethylimidazo[4,5- f]quinoxaline (NOH-MeIQx-N2-Gl). The latter product is a conjugate of the genotoxic metabolite 2-(hydroxyamino)-3,8-dimethylimidazo- [4,5- f]quinoxaline (NHOH-MeIQx). A large interindividual variation was observed in the metabolism and disposition of MeIQx; these four metabolites and unchanged MeIQx combined accounted for 6.3-26.7% of the total dose. The remaining principal metabolite found in all subjects accounted for 7.6-28% of the dose. It has not been previously identified in rodents or nonhuman primates, and its structure remains unknown. P450-mediated ring oxidation of MeIQx at the C-5 position, a major pathway of detoxication in rodents, was not detected in humans. Both 8-CH2OH-MeIQx formation and NHOH-MeIQx formation are catalyzed by P450 1A2 and may be useful biomarkers of P450 1A2 activity in humans. The levels of NHOH- MeIQx-N2-Gl found in human urine ranged from 1.4% to 10.0% of the dose, which is significantly higher than that formed in rodents and nonhuman primates undergoing cancer bioassays. Thus, bioactivation of MeIQx by P450-mediated N-oxidation is extensive in humans.

Original languageEnglish (US)
Pages (from-to)217-225
Number of pages9
JournalChemical Research in Toxicology
Volume11
Issue number3
DOIs
StatePublished - 1998
Externally publishedYes

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

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    Turesky, R. J., Garner, R. C., Welti, D. H., Richoz, J., Leveson, S. H., Dingley, K. H., Turteltaub, K. W., & Fay, L. B. (1998). Metabolism of the food-borne mutagen 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline in humans. Chemical Research in Toxicology, 11(3), 217-225. https://doi.org/10.1021/tx9701891