The Effect of Cancer Chemopreventive Agents on DNA Adduct Formation by the Dietary Prostate Carcinogen PhIP
Annual rept. 1 Apr 2000-31 Mar 2001
LAWRENCE LIVERMORE NATIONAL LAB CA CHEMISTRY AND MATERIALS SCIENCE DEPT
Pagination or Media Count:
This proposal aims to investigate chemopreventive strategies to reduce the genotoxic effects of the prostate carcinogen 2-amino-i- methyl-6-phenylimidazo4,5-Bpyridine PhIP. PhIP is considered to pose a significant prostate cancer risk to humans because it is found in cooked meat and epidemiology studies have linked meat consumption to prostate cancer. Importantly, PhIP causes prostate cancer in rats following high-dose exposures. Therefore, our purpose is to use the rat model to determine the risk posed by PhIP at levels found in the diet and to identify candidate chemopreventive agents that could be used to reduce prostate cancer risk as a result of exposure to PhIP. Consequently, we have determined that PhIP is bioavailable to the prostate at dietary levels of exposure, where it damages DNA through the dose-dependent formation of DNA adducts. The mechanism leading to adduct formation may be bioactivation to N-OH PhIP, which reaches the prostate via the circulation. Treatment of animals with PEITC, an isothiocyanate, reduced the genotoxic effects of PhIP and may be useful in the prevention of PhiP-induced prostate cancer. Consequently, this work has provided further evidence linking PhIP to the development of human prostate cancer and may lead to the identification of effective chemopreventive strategies.
- Medicine and Medical Research