Standard North American cooking processes such as broiling, frying, and barbecuing of protein-rich foods induce the formation of potent mutagenic and carcinogenic heterocyclic amines. These same compounds produced tumors at multiple organ sites in both mice and rats. Most notably, colon, prostate, and breast tumors were induced in rats. Nonhuman primates have all developed (100 percent) hepatocarcinomas after an extremely short latency following feeding of one of these heterocyclic amines, IQ. In addition, two recent findings suggest a greater risk from these compounds than thought previously: Higher levels of heterocyclic amines than seen before are generated in barbecued chicken breast; and these heterocyclic amines form DNA adducts in human colon at higher rates per dose unit than the rodent. Furthermore, epidemiology studies strongly suggest that there is a correlation of well-done meat consumption with a number of cancers in humans. Because of these findings it is important to determine the extent these mutagens/carcinogens contribute to human cancer incidence. This proposal will attempt to answer this question by: 1) Identifying and quantifying the human intake of these heterocyclic amines in the diet and the role of preventative foods; 2) Understanding the toxicology of these compounds by analysis of DNA binding, cytogenetic damage, cancer gene targets and mutational effects following acute and chronic long-term feeding of rodents; 3) Understanding the mechanistic relevance of animal studies for humans by characterizing important metabolic pathways (rodents and humans) with the additional goal of understanding the relationship of these pathways and metabolic profiles to genetic and cancer risk in humans and rat; 4) Understanding the dose-relevance of high dose animal studies for human risk assessment by assessing the DNA adduct dosimetry from ingestion of these potent mutagens at low doses. This will be accomplished utilizing an accelerator mass spectrometer, the most sensitive tool known to date, to examine low-dose DNA binding and metabolism; 5) Identifying and validating biomarkers including urine metabolic profiles that may be useful for human risk estimates or susceptibility determinations; 6) Evaluating human cancer susceptibility by evaluating cooking practices, intake of HAs, metabolic capacity, urine metabolite profiles and prostate PSA levels in a small trial population (University of Arkansas) and an African-American prostate cancer population; and 7) Characterizing the structural features of carcinogens and DNA adducts, and proteins involved in the metabolism of HAs that are correlated with mutation. All of these efforts should result in a much better understanding of the risk these carcinogenic compounds play in human cancer. Six Projects and four Cores are presented to accomplish these tasks.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA055861-12S1
Application #
7126150
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Ogunbiyi, Peter
Project Start
1992-05-01
Project End
2007-01-31
Budget Start
2005-09-26
Budget End
2006-01-31
Support Year
12
Fiscal Year
2005
Total Cost
$67,406
Indirect Cost
Name
Lawrence Livermore National Laboratory
Department
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
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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
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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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