Heat processing and pyrolysis of protein-rich foods along with standard American cooking practices such as broiling, frying and barbecuing of meats induce the formation of potent mutagenic and carcinogenic heterocyclic amines. These same compounds produced tumors at multiple organ sites in both mice and rats. Nonhuman primates fed one of these heterocyclic amines have developed hepatocarcinomas after a very short latency. Furthermore, epidemiology studies suggest a good correlation of meat consumption with cancer in humans. Because of these findings, it is important to determine whether these mutagens/carcinogens contribute to human cancer incidence. This proposal will attempt to do so by: 1) Identifying and quantifying dietary exposure to these heterocyclic amines; 2) Exploring practical methods of reducing exposure by preventing mutagen formation; 3) Understanding the chronic toxicology of these compounds by analysis of DNA binding, cytogenetic damage and mutational effects following long-term feeding of rodents; 4) Studying the importance of individual human differences in repair and metabolism by assessment in CHO cells having genetic differences in DNA repair and metabolic activation; 5) Characterizing important metabolic pathways with the goal of understanding the nature of the tissue-specific carcinogenesis induced by these heterocyclic amines in rodents and in nonhuman primates; 6) Understanding the biological dosimetry related to the low-dose exposures from the ingestion of these potent mutagens; 7) Subjecting data generated from this project and data from the literature to cancer-risk assessment. At the conclusion of this study, basic mechanisms of cytogenetic damage, metabolism and DNA adduction caused by these compounds will be more thoroughly understood. In addition, a risk assessment based on exposure, dosimetry, and pharmacokinetics will be developed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055861-07
Application #
2871768
Study Section
Subcommittee G - Education (NCI)
Program Officer
Seifried, Harold E
Project Start
1992-05-01
Project End
2001-01-31
Budget Start
1999-02-08
Budget End
2000-01-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Lawrence Livermore National Laboratory
Department
Anatomy/Cell Biology
Type
Organized Research Units
DUNS #
827171463
City
Livermore
State
CA
Country
United States
Zip Code
94550
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Bogen, K T; Keating 2nd, G A; Chan, J M et al. (2007) Highly elevated PSA and dietary PhIP intake in a prospective clinic-based study among African Americans. Prostate Cancer Prostatic Dis 10:261-9
Keating, Garrett A; Bogen, Kenneth T; Chan, June M (2007) Development of a meat frequency questionnaire for use in diet and cancer studies. J Am Diet Assoc 107:1356-62
Keating, G A; Bogen, K T (2004) Estimates of heterocyclic amine intake in the US population. J Chromatogr B Analyt Technol Biomed Life Sci 802:127-33
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Bogen, K T; Enns, L; Hall, L C et al. (2001) Gel microdrop flow cytometry assay for low-dose studies of chemical and radiation cytotoxicity. Toxicology 160:5-10
Keating, G A; Bogen, K T (2001) Methods for estimating heterocyclic amine concentrations in cooked meats in the US diet. Food Chem Toxicol 39:29-43
Hatch, F T; Knize, M G; Colvin, M E (2001) Extended quantitative structure-activity relationships for 80 aromatic and heterocyclic amines: structural, electronic, and hydropathic factors affecting mutagenic potency. Environ Mol Mutagen 38:268-91
Hatch, F T; Lightstone, F C; Colvin, M E (2000) Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity. Environ Mol Mutagen 35:279-99
Matsumoto, K; Tucker, J D (1998) Detection of structural chromosome damage in rat interphase cells using region-specific fluorescence in situ hybridization probes developed by microdissection. Mutat Res 421:179-90

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