Abstract

The overall objective of this research is to determine how carcinogenic polycyclic aromatic hydrocarbons bind to DNA in cell cultures from different species and the relationship of this binding to the induction of biological effects. This will be accomplished by analyzing the hydrocarbon-DNA interaction products formed in cell cultures from several species by both immobilized boronate chromatography and high-pressure liquid chromatography to determine the nature of the adducts formed and the relative persistence of specific adducts. Identification of the structures of the hydrocarbon-DNA adducts will be carried out directly by the application of mass spectrometric techniques as well as by radioisotope studies involving hydrolysis and chromatography. Based upon the types of hydrocarbon-DNA adducts formed, cells from various species will be selected for use as activators in mammalian cell-mediated mutation assays. The V79 target cells will be separated from the activator cells by an immunoseparation procedure and the hydrocarbon-DNA adducts formed in the target cells will be analyzed. The relationship of the formation of specific hydrocarbon-DNA adducts to the induction of mutation and cytotoxicity will be investigated. The carcinogenic hydrocarbons to be studied include both the unsubstitutedd hydrocarbon benzo(a)pyrene and the methyl-substituted, extremely potent carcinogen 7, 12-dimethylbenz(a)anthracene. At present very little is known about the role of specific 7,12-dimethylbenz(a)anthracene-DNA adducts in the induction of biological effects. The proposed studies will determine how these hydrocarbons interact with DNA, how these interactions vary in cells from different species and how specific types of hydrocarbon-DNA interactions are related to the induction of biological effects. This information will help to establish which types of hydrocarbon-DNA interactions are important for carcinogenesis and what characteristics would make a cell, tissue or species susceptible to these types of hydrocarbon-DNA interactions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA040228-01
Application #
3179904
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1985-07-01
Project End
1990-05-31
Budget Start
1985-07-01
Budget End
1986-05-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Purdue University
Department
Type
Schools of Pharmacy
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907

  Publications

Floyd, Robert A (2009) Serendipitous findings while researching oxygen free radicals. Free Radic Biol Med 46:1004-13
Baird, William M; Hooven, Louisa A; Mahadevan, Brinda (2005) Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ Mol Mutagen 45:106-14
Okazaki, Takao; Laali, Kenneth K; Zajc, Barbara et al. (2003) Stable ion study of benzo[a]pyrene (BaP) derivatives: 7,8-dihydro-BaP, 9,10-dihydro-BaP and its 6-halo derivatives, 1- and 3-methoxy-9,10-dihydro-BaP-7(8H)-one, as well as the proximate carcinogen BaP 7,8-dihydrodiol and its dibenzoate, combined with a co Org Biomol Chem 1:1509-16
Mahadevan, Brinda; Dashwood, Wan-Mohaiza; Luch, Andreas et al. (2003) Mutations induced by (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide of dibenzo[a,l]pyrene in the coding region of the hypoxanthine phosphoribosyltransferase (Hprt) gene in Chinese hamster V79 cells. Environ Mol Mutagen 41:131-9
Buters, Jeroen T M; Mahadevan, Brinda; Quintanilla-Martinez, Leticia et al. (2002) Cytochrome P450 1B1 determines susceptibility to dibenzo[a,l]pyrene-induced tumor formation. Chem Res Toxicol 15:1127-35
Mahadevan, B; Luch, A; Seidel, A et al. (2001) Effects of the (-)-anti-11R,12S-dihydrodiol 13S,14R-epoxide of dibenzo. Carcinogenesis 22:161-9
Melendez-Colon, V J; Luch, A; Seidel, A et al. (2000) Formation of stable DNA adducts and apurinic sites upon metabolic activation of bay and fjord region polycyclic aromatic hydrocarbons in human cell cultures. Chem Res Toxicol 13:7-Oct
Melendez-Colon, V J; Luch, A; Seidel, A et al. (1999) Comparison of cytochrome P450- and peroxidase-dependent metabolic activation of the potent carcinogen dibenzo[a,l]pyrene in human cell lines: formation of stable DNA adducts and absence of a detectable increase in apurinic sites. Cancer Res 59:1412-6
Luch, A; Kishiyama, S; Seidel, A et al. (1999) The K-region trans-8,9-diol does not significantly contribute as an intermediate in the metabolic activation of dibenzo[a,l]pyrene to DNA-binding metabolites by human cytochrome P450 1A1 or 1B1. Cancer Res 59:4603-9
Luch, A; Kudla, K; Seidel, A et al. (1999) The level of DNA modification by (+)-syn-(11S,12R,13S,14R)- and (-)-anti-(11R,12S,13S,14R)-dihydrodiol epoxides of dibenzo[a,l]pyrene determined the effect on the proteins p53 and p21WAF1 in the human mammary carcinoma cell line MCF-7. Carcinogenesis 20:859-65

Showing the most recent 10 out of 38 publications