Thomas M. Harris
Dr. Harris is a member and currently associate director of Vanderbilt's Center of Molecular Toxicology. The chemical basis of the genotoxicity of man-made and naturally occurring environmental carcinogens is being investigated in his laboratory. A central thrust of the research involves devising strategies for preparation of DNA to which carcinogens are bound in a structurally specific manner. Additional interests include mechanistic studies of the reactions of carcinogens with DNA, structural studies of DNA bearing the carcinogen adducts, and the implications of these findings for the carcinogenic process.
One project centers on the fungal metabolite aflatoxin B1. This powerful carcinogen is a common contaminant of peanuts and other agricultural commodities. The goals of the project are to understand why the compound reacts so efficiently with DNA and why the adducts are so potently mutagenic. Dr. Harris has synthesized the long-sought active form, the 8,9-epoxide, and has been studying its interactions with DNA. These studies include determination of the structures of the various DNA adducts, 2-dimensional NMR studies of the adducts in duplexed DNA to elucidate conformations, and investigations of the mechanisms by which the adducts are formed.
Another project involves the carcinogenic polycyclic aromatic hydrocarbons (PAHs) formed during food preparation, cigarette smoking and from incomplete combustion of fuels. Synthetic strategies are being developed for preparation of oligonucleotides bearing regio- and stereospecifically placed adducts of PAH diol epoxides so that the effect of adduct structure on DNA conformation and replication fidelity can be assessed.
A final project involves the synthesis of DNA crosslinks that arise by the reaction of DNA with bis-electrophiles. Examples include crosslinks formed by activated forms of the retronecine alkaloids and of butadiene. Interchain crosslinks are blocks to replication but can become a source of mutations during enzymatic repair.