The objective of this proposal is to determine the modes of metabolic activation of the carcinogenic non-alternate polynuclear aromatic hydrocarbon carcinogens benzo-(b)fluoranthene, benzo(j)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)pyrene, and 2- and 3-methylfluoranthene. The bay region theory of activation of carcinogenic PAH has been shown to apply to several alternate hydrocarbons. Our studies on the metabolic activation of these six non-alternate PAH indicate that there is little or no similarity in their activation pathways. This program has as its overall objective to elucidate the mechanism of activation of these select PAH which are of particular interest because of actual human exposure. Suspect proximate and/or ultimate carcinogenic metabolites of benzo(j)fluoranthene, benzo(k)fluoranthene, indeno(1,2,3-cd)pyrene and 2- and 3-methylfluoranthene have been identified from detailed in vitro and in vivo metabolism studies. Those metabolic activation pathways believed to be associated with carcinogenic activity of these PAH will be evaluated by identification of major DNA-adducts formed in vivo in mouse skin, bioassays of suspect proximate and ultimate mutagens, and/or bioassays of select fluoro-substituted analogs. Studies on the metabolic activation of benzo(b)-fluoranthene suggest that multiple sites on this molecule are associated with its carcinogenicity. Fluorescence spectra of isolated DNA adducts as formed in vivo in mouse skin and a limited study on the effect of fluoro-substitution at specific positions of benzo(b) fluoranthene on tumorigenic activity will be employed to elucidate the mechanism(s) of activation associated with its carcinogenicity. These studies will lead to the elucidation of the mechanism of action of several of these carcinogenic non-alternate PAH, which are ubiquitous in the environment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
2R01ES002030-07
Application #
3249662
Study Section
Toxicology Study Section (TOX)
Project Start
1978-12-05
Project End
1988-02-29
Budget Start
1985-03-01
Budget End
1986-02-28
Support Year
7
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Institute for Cancer Prevention
Department
Type
DUNS #
City
Valhalla
State
NY
Country
United States
Zip Code
10595
Dowd, T L; Rosen, J F; Li, L et al. (2003) The three-dimensional structure of bovine calcium ion-bound osteocalcin using 1H NMR spectroscopy. Biochemistry 42:7769-79
Dowd, T L; Rosen, J F; Mints, L et al. (2001) The effect of Pb(2+) on the structure and hydroxyapatite binding properties of osteocalcin. Biochim Biophys Acta 1535:153-63
LaVoie, E J; He, Z M; Wu, Y et al. (1994) Tumorigenic activity of the 4,5- and 9,10-dihydrodiols of benzo[j]fluoranthene and their syn- and anti-diol epoxides in newborn mice. Cancer Res 54:962-8
LaVoie, E J; Cai, Z W; Meschter, C L et al. (1994) Tumorigenic activity of fluoranthene, 2-methylfluoranthene and 3-methylfluoranthene in newborn CD-1 mice. Carcinogenesis 15:2131-5
Weyand, E H; Bryla, P; Wu, Y et al. (1993) Detection of the major DNA adducts of benzo[j]fluoranthene in mouse skin: nonclassical dihydrodiol epoxides. Chem Res Toxicol 6:117-24
LaVoie, E J; Cai, Z W; Meegalla, R L et al. (1993) Evaluation of the tumor-initiating activity of 4-, 5-, 6-, and 7-fluorobenzo[b]fluoranthene in mouse skin. Chem Biol Interact 89:129-39
Marshall, M V; He, Z M; Weyand, E H et al. (1993) Mutagenic activity of the 4,5- and 9,10-dihydrodiols of benzo[j]fluoranthene and their syn- and anti-dihydrodiol epoxides in Salmonella typhimurium. Environ Mol Mutagen 22:34-45
LaVoie, E J; He, Z M; Meegalla, R L et al. (1993) Exceptional tumor-initiating activity of 4-fluorobenzo[j]-fluoranthene on mouse skin: comparison with benzo[j]-fluoranthene, 10-fluoro-benzo[j]fluoranthene, benzo[a]pyrene, dibenzo[a,l]pyrene and 7,12-dimethylbenz[a]anthracene. Cancer Lett 70:7-14
Weyand, E H; Cai, Z W; Wu, Y et al. (1993) Detection of the major DNA adducts of benzo[b]fluoranthene in mouse skin: role of phenolic dihydrodiols. Chem Res Toxicol 6:568-77
Weyand, E H; He, Z M; Ghodrati, F et al. (1992) Effect of fluorine substitution on benzo[j]fluoranthene genotoxicity. Chem Biol Interact 84:37-53

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