b Carotene Isomers and Retinol as Anticarcinogens

University Of Missouri-Rolla, Rolla MO

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Abstract

DESCRIPTION (provided by applicant): Enhanced generation of reactive oxygen intermediates (ROI) during prolonged exposure to prooxidants such as radiation and environmental toxins can overwhelm cell's intrinsic antioxidant defenses, and result in a condition known as "oxidative stress." Cells under oxidative stress display various dysfunctions due to lesions caused by ROI to lipids, proteins and DNA. Free radical-induced DNA damage alters the genotype of cells leading to carcinogenesis. A comparative study of the anticarcinogenicity among geometrical beta-carotene isomers (present in fruits and vegetables) and retinol has not been carried out before. The objectives of this proposal are: (a) to synthesize or isolate pure cis isomers of beta-carotene (15-cis, 13-cis, 9-cis, 9,15-dicis, and 9,9',15-tricis); (b) to measure the rates of the reaction of the above geometrical beta-carotene isomers and retinol with radicals involved in carcinogenesis such as superoxide (O2.-) and hydroperoxyl radical (HO2.), in order to identify the best radical trap. (We have demonstrated that both radicals can be generated electrochemically, and that the relevant rate constants can be measured with cyclic voltammetry.); (c) to carry out a comparative biological testing of the various beta-carotene isomers and retinol, both in vitro (cell culture-based assays) and in vivo (mice), in order to elucidate the protective effect of any given beta-carotene isomer and retinol on irradiated cells and tissues by directly measuring the parameters of oxidative stress. Overall, this project aims in identifying the most effective natural anticancer agent (radical trap) among the beta-carotenes and retinol. Based on the results of this work, the medical community would be advised to respond to the ineffectiveness of studies using one stereoisomer, all-trans-beta-carotene, by strongly encouraging the performance of epidemiological studies using a chemically more rational approach.