Aflatoxins represent a group of closely related natural chemicals produced by the common fungal molds, Aspergillus flavus and Aspergillus parasiticus. Worldwide, aflatoxins are considered a major public health problem, especially in developing countries where high heat and humidity favor the growth of the mold, and food storage is inadequate. There is substantial experimental animal and human epidemiological data supporting a causative role of aflatoxins in the unusually high incidence of liver cancer in some areas of the world. Numerous studies have demonstrated that there are large species differences in the susceptibility to aflatoxin carcinogenesis. Rats are highly sensitive, whereas mice are very resistant. The mechanism for this difference has been determined to be associated with the expression of a specific enzyme, called glutathione S-transferase Yc, which is present in the livers of mice, but not rats. However, it has been found that treatment of rats with a drug called oltipraz, or a food additive called ethoxyquin, protects rats from aflatoxin-induced liver cancer when given before aflatoxin. The mechanism for this protection is due to the ability of these chemicals to """"""""turn on"""""""" a gene for a Yc glutathione S-transferase that is normally not expressed in rat liver, but which efficiently detoxifies aflatoxin. Human liver tissue has very low ability to detoxify aflatoxin -- in fact, worse than the poor ability of rats. It has been proposed that human could be made relatively resistant to the cancer-causing effects of aflatoxin by giving oltipraz, but this presumes that humans, like rats, have a form of glutathione S-transferase in their genes which is not normally expressed in liver, but could be induced by chemicals such as oltipraz and/or ethoxyquin. The long-range goals of this grant is to determine the specific structural characteristics of the glutathione S-transferase Yc enzyme that confers high aflatoxin detoxifying ability, and to then evaluate whether such an enzyme might be present in humans, and determine whether treatment with oltipraz or ethoxyquin will ultimately enhance detoxification of aflatoxin in humans.
The specific aims of this grant are to: I) Complete the molecular characterization of glutathione S- transferases with high catalytic activity toward AFB-epoxide which could be used to establish a """"""""consensus amino acid sequence"""""""" in alpha class GSTs which confers high catalytic activity toward aflatoxin; 2) Fully characterize CYP45O-mediated oxidation of aflatoxin; 3) Further. evaluate the metabolism of AFB in various species, including humans and non-human primates, using precision liver slices; 4) Use an in vivo non-human primate model to evaluate the effectiveness of oltipraz and ethoxyquin to reduce aflatoxin carcinogenesis in humans. the results of these studies should further enhance our understanding of: 1) how chemicals produce cancer in humans and laboratory animals; 2) the importance of understanding mechanisms of chemical biotransformation in humans and common laboratory species to better predict chemical carcinogenesis in humans from rodent studies, and 3) whether proposed chemical and/or dietary intervention strategies to reduce aflatoxin-induced cancer might be expected to work.
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