The objectives of this biochemical research are 1) to critically test the structure-activity relationship theory developed in this laboratory over the past 20 years, 2) to increase our understanding of the nature of the reactions that are involved in the metabolic activation of polynuclear aromatic hydrocarbons, and 3) to understand the reasons for the striking structure-activity relationships in this class of compounds. The metabolism of a series of closely related hydrocarbons will be investigated and compared, using HPLC, GC/MS, and 32P postlabelling and a number of reference compounds, and their activation to electrophilic intermediates that react with nucleic acids will be studied, in vitro and in vivo, in rat liver, lung, and subcutaneous tissue. We expect to be able to distinguish between the reactions of the hydrocarbons leading to carcinogenesis and the reactions leading to inactivation. The long term objectives of these studies are 1) to correctly predict the carcinogenicity of a polynuclear aromatic hydrocarbon from a knowledge of its features of structure and metabolism, and 2) to assess, in metabolism studies, the susceptibility of subcutaneous tissue, in comparison with lung and liver, to carcinogenesis by polynuclear aromatic hydrocarbons. A more complete understanding of the most important structural features and reactions involved in polynuclear aromatic hydrocarbon carcinogenesis may eventually lead to methods for the prevention of some of the human cancer that is currently considered to be caused by this class of chemical carcinogens.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Flesher, J W; Horn, J; Lehner, A F (1998) Carcinogenicity of 1-hydroxy-3-methylcholanthrene and its electrophilic sulfate ester 1-sulfooxy-3-methylcholanthrene in Sprague-Dawley rats. Biochem Biophys Res Commun 243:30-5
Flesher, J W; Horn, J; Lehner, A F (1997) 7-Sulfooxymethyl-12-methylbenz[a]anthracene is an exceptionally reactive electrophilic mutagen and ultimate carcinogen. Biochem Biophys Res Commun 231:144-8
Flesher, J W; Horn, J; Lehner, A F (1997) 6-sulfooxymethylbenzo[a]pyrene is an ultimate electrophilic and carcinogenic form of the intermediary metabolite 6-hydroxymethylbenzo[a]pyrene. Biochem Biophys Res Commun 234:554-8
Flesher, J W; Horn, J; Lehner, A F (1997) 7-Sulfooxymethylbenz[a]anthracene is an ultimate electrophilic and carcinogenic form of 7-hydroxymethylbenz[a]anthracene. Biochem Biophys Res Commun 231:712-6
Horn, J; Flesher, J W; Lehner, A F (1996) 1-Sulfooxymethylpyrene is an electrophilic mutagen and ultimate carcinogen of 1-methyl- and 1-hydroxymethylpyrene. Biochem Biophys Res Commun 228:105-9
Stansbury, K H; Flesher, J W; Gupta, R C (1994) Mechanism of aralkyl-DNA adduct formation from benzo[a]pyrene in vivo. Chem Res Toxicol 7:254-9
Myers, S R; Flesher, J W (1991) Metabolism of chrysene, 5-methylchrysene, 6-methylchrysene and 5,6-dimethylchrysene in rat liver cytosol, in vitro, and in rat subcutaneous tissue, in vivo. Chem Biol Interact 77:203-21
Flesher, J W; Myers, S R (1991) Methyl-substitution of benzene and toluene in preparations of human bone marrow. Life Sci 48:843-50
Flesher, J W; Myers, S R (1991) Rules of molecular geometry for predicting carcinogenic activity of unsubstituted polynuclear aromatic hydrocarbons. Teratog Carcinog Mutagen 11:41-54
Myers, S R; Flesher, J W (1991) Bioalkylation of benz[a]anthracene, 7-methylbenz[a]anthracene, and 12-methylbenz[a]anthracene in rat lung cytosol preparations. Biochem Pharmacol 41:1683-9

Showing the most recent 10 out of 15 publications