SPECIES DIFFERENCE IN THE BIOTRANSFORMATION OF AFLATOXIN
Principal Investigator: David Eaton
Affiliation: University of Washington
Abstract: Numerous studies have demonstrated that biologically active, natural components of the diet may confer resistance to chemical carcinogens via induction and/or inhibition of biotransformation enzymes. In particular, specific chemical components of the diet, such as flavonoids, isocyanates, glucosinolates, indoles, dithiolthiones, and polyphenols have been identified as effective inducers and/or inhibitors of carcinogen activation/detoxification pathways in animal models. There is much supporting data from human epidemiological studies on the important relationship between diet and cancer in humans, although the diversity and complexity of the diet, and uncertainty of specific exposures, in such studies makes identification of specific active components nearly impossible. Although animal models are useful for "hypothesis testing", species differences in carcinogen activation and detoxification pathways, as well as differences in gene regulation and expression in response to inducers, make extrapolation of animal data to the human situation tentative, at best. Thus, there is a need to develop model systems that utilize human cells/tissues to determine the efficacy of specific dietary components and/or putative chemoprotectant drugs to favorably modify the biotransformation of human carcinogens. One such model human carcinogen is aflatoxin B1. Aflatoxins are mycotoxins produced by the common fungal molds, Aspergillus flavus and Aspergillus parasiticus. Worldwide, aflatoxins are considered a major public health problem because of their potent carcinogenic effects. Human epidemiological data has documented that humans are susceptible to AFB-induced hepatocarcinogenesis, especially in combination with hepatitis B virus infection. However, 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 is associated with the expression of a specific enzyme, glutathione S-transferase A3-3 (mGSTA3-3), which is present in the livers of mice, but not rats. Treatment of rats with the drug, oltipraz, or the food additive, ethoxyquin, protects rats from aflatoxin-induced liver cancer. The mechanism for this protection is due to the ability of these chemicals to "turn on" a gene for a glutathione S-transferase, rGSTA5-5, 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. There has been considerable interest in devising a dietary or chemointervention strategy for humans that increases resistance to AFB by induction of GSTs. The long range goals of this proposal are to: 1) establish in vitro models that utilize isolated human hepatocytes in culture and human cDNA expressing yeast, to assess the efficacy of specific dietary components as putative chemoprotectors against AFB and other chemical carcinogens, and 2) complete the characterization of species differences in glutathione S-transferases with activity toward AFB-epoxide.
Funding Period: 1991-05-01 - 2005-07-31
more information: NIH RePORT
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Departmental of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105 6099, USA
Mol Cell Biol 25:5823-33. 2005..Rev3 appears to mediate AFB1-induced mutagenesis when error-free pathways are compromised. The results further suggest unique roles for Rad5 and abasic endonuclease-dependent DNA intermediates in regulating AFB1-induced mutagenicity...
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Department of Environmental and Occupational Health Sciences, Center for Ecogenetics and Environmental Health, University of Washington, Seattle, WA 98105, USA
Xenobiotica 35:419-38. 2005..5. It is concluded that an Matrigel overlay facilitates the maintenance and induction of xenobiotic metabolizing enzymes in primary cultures of human hepatocytes...
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Departmental of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
Mutat Res 593:121-42. 2006....
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Interdisciplinary Graduate Program in Nutritional Sciences, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA 98195 4695, USA
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Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA
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Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA
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