ACTIVATION OF 4-HYDROXY TAMOXIFEN TO FORM DNA ADDUCTS

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DESCRIPTION: (Adapted from the investigator's abstract) Tamoxifen (TMX) is an antiestrogenic compound used in the treatment of breast cancer. Recent clinica studies indicate that women treated with TMX have up to a 6-fold increased ris of uterine cancer. Results from Dr. Bodell's laboratory suggest that the metabolite 4-hydroxy-tamoxifen (4-OH-TMX) may be playing an important role in this process. In the proposed studies he will assess the activation of 4-OH-TM to form DNA adducts. He believes that these studies will provide new insights as to the mechanisms by which TMX increases the risk of uterine cancer. Dr. Bodell proposes: [1] To use liver and uterine microsomal activation systems an uterine peroxidase to investigate the further oxidation of 4-OH-TMX. The proposed quinone methide (QM) product will be trapped as DNA adducts. The reduction of 4-OH-TMX (QM) by DT-diaphorase will be examined. The goals of these studies are to investigate the role(s) of P450, uterine peroxidase and DT-diaphorase in the activation and detoxification of 4-OH-TMX and to define the reactive intermediate of 4-OH-TMX leading to adduct formation. [2] To investigate the accumulation of metabolites and DNA adducts in tissues of female Sprague-Dawley rats treated with either TMX or the non-carcinogenic analogue Toremifine. The dose and treatment schedule will be the same as those shown to induce endometrial cancer in Sprague-Dawley rats. The effects of the chemopreventive agent Oltipraz on the formation of DNA adducts by TMX will be determined. These studies will provide important information on the role of DN adducts in the etiology of endometrial cancer induced by TMX administration. [3] To optimize the 32P-postlabeling procedure for 4-OH-TMX. These identified adducts will be used to investigate the DNA adducts formed by microsomal and peroxidase activation of 4-OH-TMX and the adduct detected in uterine tissues o rat treated with TMX. Direct analysis of the adduct(s) detected in uterine samples of rats treated with TMX will be made by electrospray ionization mass spectrometry.