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Stephen F. Nelsen
65th Birthday Symposium
Madison, Wisconsin
June 3-4, 2005
West Virginia University, Basic Pharmaceutical Sciences, PO Box 9530, Morgantown, WV 26506
The role of aryl radicals and Z DNA in arylhydrazine carcinogenisis
Many arylhydrazines are carcinogenic. Sources of these compounds include both man-made, such as pharmaceutical agents, and natural sources. Their mechanism of action as carcinogens is poorly understood. We have found that the metabolic activation of arylhydrazines results in the formation of arene diazonium ions and aryl radicals. In turn, these intermediates react with the purine bases of DNA to form C8-aryladenine and C8-arylguanine adducts. Our studies of these C8-arylation adducts of purines in DNA show that they have profound affects on the conformational preferences of DNA, destabilizing B DNA and stabilizing Z DNA. A role for Z DNA in carcinogenesis has been reported and be the source of arylhydrazine carcinogenesis. The metabolic activation, purine arylation, and remarkable affect on DNA conformation will be discussed.
Last Updated: January 10, 2005 (P.M. Gannett)