Our laboratory has been characterizing bioactivation of carcinogens in the prostate, a tissue with limited cytochrome P450 activity. This proposal is based on our identification of a novel molecular target for nutrients in the prostate, which is a protein that oxidizes prostate carcinogens to DNA-reactive metabolites. We have discovered that several important nutrients, in particular, ferulic acid, vanillic acid and epigallocatechin gallate, are effective and potent inhibitors of this enzyme. Thus, by inhibiting this highly specific target and blocking the activation of prostate carcinogens, nutrients display chemopreventative activity, cDNA clones of the target protein have been obtained and cells overexpressing the oxidase characterized. Four major genotoxic chemicals have been identified that induce prostate tumors when administered to rodents: 3,2'-dimethyl-4-aminobiphenyl (DMAB), 2-amino-l-methyl-6-phenyl-imidazo(4,5- b)pyridine (PhIP), N-nitrosobis (2-oxopropyl) amine and N-methyl-nitrosourea. PhIP is a heterocyclic amine produced during cooking that has only recently been identified as a prostate carcinogen, while DMAB, a synthetic aromatic amine, is a member of a large family of aminobiphenyls synthesized by the chemical dye industry. We hypothesize that dietary nutrients alter prostate carcinogen metabolism by blocking the activity of the novel oxidase that activates these compounds. To test this hypothesis, the ability of our novel oxidase activity to metabolize DMAB will be evaluated. We will also assess the effects of dietary nutrients on this enzyme activity in prostate cells. These studies will provide important information on a unique target for chemopreventative agents in the prostate.
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