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Synthetic and naturally occurring phenolic antioxidants have a wide variety of biological actions in rodents in addition to their primary antioxidant activity. Some of the included biological effects are of direct interest in relation to studies of carcinogenicity and/or modulation af carcinogenesis. Since the synthetic phenolic antioxidant BHA was first found to exert carcinogenic potential in rat and hamster forestomach epithelium, ninny other synthetic and naturally occurring antioxidants have been examined for their ability to induce proliferative activity in the alimentary canal. It was revealed theat caffeic acid and sesamol are also tumorigenic for rat forestomach epithelium, whereas catechol and 4-methylcatechol induce neoplasia in rat glandular stomach epithelium. Although the proliferative response is very rapid, with inflammation and ulceration. it takes a very long time before carcinomas develop. The proliferative lesions in the forestomach induced by BHA or caffeic acid are largely reversible, in contrast to those induced by genotoxic carcinogens, which generally persist and develop into cancer. Therefore, chronic irritation is considered to be responsible for the induction of stomach cancer by phenolic antioxidants. Neither BHA nor its metabolites binds io DNA in vivo, but protein binding in the forestomach was $gt;10 times higher than that in the glandular stomach. It is thus conceivable that BHA is oxidatively metabolized in the forestomach epithelium(possible entering into redox cycling) and reactive metabolites including semiquinone radical, ar active oxygen species are responsible for the carcinogenesis by a mechanism involving binding to macromolecules. Many phenolic antioxidants have been shown to modify carcinogenesis and as a rule. they inhibit the initiation stage by reducing the interaction between carcinogen and DNA. However, both promotion and inhibition have been reported for second-stage carcinogenesis, depending on the organ site, species of animal, or initiating carcinogen.
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