Methods will be developed and validated for quantifying human exposure to, and metabolism of, potent mutagens. We will focus on aminoimidazoazaarenes (AIA), chemical mutagens formed in meats by cooking and therefore widely consumed in the American diet. These chemicals are potent mutagens in the Ames/Salmonella assay and, where they have tested in long-term bioassays, are carcinogens. It is only in the past five years that these compounds have been isolated, identified, and synthesized in sufficient quantities for studies on their mechanisms of action. The next logical step in determining the human health risk posed by these chemicals requires quantification of their uptake, metabolism, and clearance rates in humans. In many ways the exposure to cooked-meat mutagens is prototypic of environment and occupational exposures to aromatic amines. There is chronic low level exposure to low doses of a complex mixture of chemicals. Individuals differ both in their exposures and in their ability to activate the compounds to potentially reactive electrophiles. Our studies will provide a comprehensive integration of several new methods for biochemical dosimetry. We already have monoclonal antibodies for the parent AIA compounds, and these cross react with some metabolites. We will incorporate these antibodies into immunoassays and validate the assays for the deletion of AIAs and AIA metabolites in human urine. An immunoassay to AIA-protein adducts will be developed and validated on adducted human serum proteins. Also, P32 post- labeling will be used to identify and quantify AIA-DNA adducts formed by humans. The markers developed under this project will permit studies on genetic and environmental influences on an individual's response to AIA exposure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA048446-03
Application #
3549197
Study Section
Special Emphasis Panel (SRC (60))
Project Start
1988-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1992-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Lawrence Livermore National Laboratory
Department
Type
Organized Research Units
DUNS #
827171463
City
Livermore
State
CA
Country
United States
Zip Code
94550
Tucker, J D; Vanderlaan, M; Kwan, T C et al. (1993) Effects of diet and folate on levels of micronucleated polychromatic erythrocytes. Mutat Res 301:19-26
Vanderlaan, M; Hwang, M; Djanegara, T (1993) Immunoaffinity purification of dietary heterocyclic amine carcinogens. Environ Health Perspect 99:285-7
Watkins, B E; Suzuki, M; Wallin, H et al. (1991) The effect of dose and enzyme inducers on the metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats. Carcinogenesis 12:2291-5
Vanderlaan, M; Alexander, J; Thomas, C et al. (1991) Immunochemical detection of rodent hepatic and urinary metabolites of cooking-induced food mutagens. Carcinogenesis 12:349-54
Wild, D; Watkins, B E; Vanderlaan, M (1991) Azido- and nitro-PhIP, relatives of the heterocyclic arylamine and food mutagen PhIP--mechanism of their mutagenicity in Salmonella. Carcinogenesis 12:1091-6
Turteltaub, K W; Watkins, B E; Vanderlaan, M et al. (1990) Role of metabolism on the DNA binding of MeIQx in mice and bacteria. Carcinogenesis 11:43-9
Vanderlaan, M; Hwang, M; Knize, M G et al. (1990) Monoclonal antibody based immunoassays for cooking-induced meat mutagens. Prog Clin Biol Res 340E:189-98
Vanderlaan, M; Watkins, B E; Hwang, M et al. (1989) Monoclonal antibodies to 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine (PhIP) and their use in the analysis of well-done fried beef. Carcinogenesis 10:2215-21