Macromolecular adduct formation and metabolism of heterocyclic amines in humans and rodents at low doses

Kenneth W. Turteltaub, Karen H. Dingley, Kellie D. Curtis, Michael A. Malfatti, Robert J. Turesky, R. Colin Garner, James S. Felton, Nicholas P. Lang

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are heterocyclic amines formed during the cooking of meat and fish. Both are genotoxic in a number of test systems and are carcinogenic in rats and mice. Human exposure to these compounds via dietary sources has been estimated to be under 1 μg/kg body wt. per day, although most laboratory animal studies have been conducted at doses in excess of 10 mg/kg body wt. per day. We are using accelerator mass spectrometry (AMS), a tool for measuring isotopes with attomole sensitivity, to study the dosimetry of protein and DNA adduct formation by low doses of MeIQx and PhIP in rodents and comparing the adduct levels to those formed in humans. The results of these studies show: 1, protein and DNA adduct levels in rodents are dose-dependent; 2, adduct levels in human tissues and blood are generally greater than in rodents administered equivalent doses; and 3, metabolite profiles differ substantially between humans and rodents for both MeIQx and PhIP, with more N-hydroxylation (bioactivation) and less ring oxidation (detoxification) in humans. These data suggest that rodent models do not accurately represent the human response to heterocyclic amine exposure. Copyright (C) 1999 Elsevier Science Ireland Ltd.

Original languageEnglish (US)
Pages (from-to)149-155
Number of pages7
JournalCancer Letters
Volume143
Issue number2
DOIs
StatePublished - Sep 1999

Bibliographical note

Funding Information:
We thank Kurt Haack (LLNL) for AMS sample preparation, Kristen Kulp (LLNL) and Mark Knize (LLNL) for purification and characterization of PhIP urinary metabolites, and Fred Kadlubar for advise in these studies. This work performed under the auspices of the US DOE (W-7405-ENG-48) and partially supported by NIH CA55861, and UK MAFF (FS1722).

Keywords

  • 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
  • 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline
  • Accelerator mass spectrometry
  • Dosimetry
  • Human
  • Rodent

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