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Rapid CommunicationShort Communication

Covalent Binding of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline to Albumin and Hemoglobin at Environmentally Relevant Doses

Comparison of Human Subjects and F344 Rats

Karen H. Dingley, Stewart P. H. T. Freeman, David O. Nelson, R. Colin Garner and Kenneth W. Turteltaub
Drug Metabolism and Disposition August 1998, 26 (8) 825-828;
Karen H. Dingley
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Stewart P. H. T. Freeman
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David O. Nelson
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R. Colin Garner
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Kenneth W. Turteltaub
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Comparison of Human Subjects and F344 Rats

Abstract

Covalent binding of the food-borne heterocyclic amine 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) to albumin and hemoglobin (Hb), 3.5–6.0 hr after oral administration of a single dose of either 21.3 or 228.0 μg of [14C]MeIQx (304 and 3257 ng/kg of body weight, respectively, based on a 70-kg subject weight), was studied in human volunteers using accelerator mass spectrometry. Human protein adduct levels were compared with data obtained for male F344 rats 4.5 hr after oral administration of 0.94–11,420 ng/kg of body weight [14C]MeIQx. Dose-dependent levels of MeIQx-albumin and MeIQx-Hb adducts were detected in both humans and rats. In each case, the regression coefficient (slope) of the dose-response curve was approximately 1. The highest levels of adduct formation per unit dose of MeIQx occurred with human albumin, followed by rat albumin, human Hb, and rat Hb (in that order). Although the human subjects were elderly and underwent colon resection surgery during the study period, the results indicate that formation of albumin and Hb adducts is dose dependent and that a trend exists for higher adduct levels per unit dose in humans, compared with F344 rats. Furthermore, MeIQx-albumin adducts are likely to provide a more sensitive marker of exposure to MeIQx than are MeIQx-Hb adducts.

Footnotes

  • Send reprint requests to: Dr. K. H. Dingley, Lawrence Livermore National Laboratory, P.O. Box 808, L-452, Livermore, CA 94551-9900.

  • The studies described were performed under the auspices of the United States Department of Energy by the Lawrence Livermore National Laboratory (Contract W-7405-ENG-48) and were partially supported by the National Institutes of Health (Grant CA55861), the US Army Medical Research and Materiel Command (Grant MM4559FLB), and the United Kingdom Ministry of Agriculture, Fisheries and Food (Grant FS1722). This work was presented at the 88th Annual Meeting of the American Association for Cancer Research (1997).

  • Abbreviations used are::
    HCA
    heterocyclic amine
    MeIQx
    2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline
    Hb
    hemoglobin
    CI
    confidence interval
    AMS
    accelerator mass spectrometry
    • Received February 3, 1998.
    • Accepted April 16, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition
Vol. 26, Issue 8
1 Aug 1998
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Rapid CommunicationShort Communication

Covalent Binding of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline to Albumin and Hemoglobin at Environmentally Relevant Doses

Karen H. Dingley, Stewart P. H. T. Freeman, David O. Nelson, R. Colin Garner and Kenneth W. Turteltaub
Drug Metabolism and Disposition August 1, 1998, 26 (8) 825-828;

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Rapid CommunicationShort Communication

Covalent Binding of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline to Albumin and Hemoglobin at Environmentally Relevant Doses

Karen H. Dingley, Stewart P. H. T. Freeman, David O. Nelson, R. Colin Garner and Kenneth W. Turteltaub
Drug Metabolism and Disposition August 1, 1998, 26 (8) 825-828;
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