Numerous previous studies have demonstrated that the common food antioxidants BHA and BHT, as well as naturally occurring substances present in a variety of vegetables, reduce the carcinogenic and toxic effects of a variety of chemical carcinogens. Recent studies have demonstrated that phenolic antioxidants reduce the covalent binding and carcinogenicity of the potent, naturally occurring dietary carcinogen, aflatoxin B1 (AFB), by inducing glutathione-S-transferases (GST). Specific forms of this enzyme appear responsible for the species differences in sensitivity to the hepatocarcinogenic effects of AFB. Some """"""""anticarcinogenic"""""""" vegetables such as broccoli and brussel sprouts are also effective inducers of GST, but also alter oxidative biotransformation pathways. Because induction of multiple biotransformation pathways can result in highly substrate-specific alterations in xenobiotics, it is essential to determine the effects of dietary treatments on actual chemical carcinogens of importance, rather than making inferences from """"""""surrogate"""""""" substrates which may behave very differently. Methods have recently been developed which allow for the determination of both the rate of oxidative formation of AFB- epoxide (the putative carcinogenic form), as well as rates of GST inactivation of the AFB-epoxide. With these methodologies it is now possible to assess the effects of dietary factors directly on the metabolic disposition of AFB. The long-range goal of this research project is to determine the biochemical mechanisms by which dietary factors such as vegetable consumption and antioxidant exposure influence carcinogen disposition. With such an understanding of mechanisms, dietary and/or chemical interventions may be rationally developed which could lead to reduction in chemical-induced cancers.
The specific aims of this project are to: 1) rigorously examine the relationship between diet-induced changes in specific hepatic biotransformation pathways and the covalent binding of the potent hepatocarcinogen aflatoxin B1 (AFB) to hepatic DNA in vivo, utilizing a) a diet containing PCBs, b) a diet containing beta-napthoflavone, c) a diet containing various concentrations of BHA (dose-response study), d) a diet containing both BHA and beta-napthoflavone, e) a diet containing 25% freeze-dried broccoli, and f) a diet containing only indoles at the same concentration as in the broccoli diet. Additional studies are also proposed to examine the structure- activity relationship between different phenolic antioxidants, enzyme induction and inhibition of AFB-DNA binding.
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