SPECIES DIFFERENCE IN THE BIOTRANSFORMATION OF AFLATOXIN

Summary

Principal Investigator: David Eaton
Affiliation: University of Washington
Country: USA
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

Top Publications

  1. pmc Expression of a human cytochrome p450 in yeast permits analysis of pathways for response to and repair of aflatoxin-induced DNA damage
    Yingying Guo
    Departmental of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105 6099, USA
    Mol Cell Biol 25:5823-33. 2005
  2. ncbi Influence of Matrigel-overlay on constitutive and inducible expression of nine genes encoding drug-metabolizing enzymes in primary human hepatocytes
    K Gross-Steinmeyer
    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
  3. ncbi Analysis of cellular responses to aflatoxin B(1) in yeast expressing human cytochrome P450 1A2 using cDNA microarrays
    Yingying Guo
    Departmental of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
    Mutat Res 593:121-42. 2006
  4. ncbi Apiaceous vegetable constituents inhibit human cytochrome P-450 1A2 (hCYP1A2) activity and hCYP1A2-mediated mutagenicity of aflatoxin B1
    Sabrina Peterson
    Interdisciplinary Graduate Program in Nutritional Sciences, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA 98195 4695, USA
    Food Chem Toxicol 44:1474-84. 2006
  5. ncbi The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor
    Changcheng Zhou
    Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA
    Mol Pharmacol 71:220-9. 2007
  6. pmc Modulation of aflatoxin B1-mediated genotoxicity in primary cultures of human hepatocytes by diindolylmethane, curcumin, and xanthohumols
    Kerstin Gross-Steinmeyer
    Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA
    Toxicol Sci 112:303-10. 2009

Detail Information

Publications6

  1. pmc Expression of a human cytochrome p450 in yeast permits analysis of pathways for response to and repair of aflatoxin-induced DNA damage
    Yingying Guo
    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...
  2. ncbi Influence of Matrigel-overlay on constitutive and inducible expression of nine genes encoding drug-metabolizing enzymes in primary human hepatocytes
    K Gross-Steinmeyer
    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...
  3. ncbi Analysis of cellular responses to aflatoxin B(1) in yeast expressing human cytochrome P450 1A2 using cDNA microarrays
    Yingying Guo
    Departmental of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
    Mutat Res 593:121-42. 2006
    ....
  4. ncbi Apiaceous vegetable constituents inhibit human cytochrome P-450 1A2 (hCYP1A2) activity and hCYP1A2-mediated mutagenicity of aflatoxin B1
    Sabrina Peterson
    Interdisciplinary Graduate Program in Nutritional Sciences, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA 98195 4695, USA
    Food Chem Toxicol 44:1474-84. 2006
    ..These results suggest that in vivo CYP1A2 inhibition by apiaceous vegetables may be due to the phytochemicals present and imply that apiaceous vegetable intake may be chemopreventive by inhibiting CYP1A2-mediated carcinogen activation...
  5. ncbi The dietary isothiocyanate sulforaphane is an antagonist of the human steroid and xenobiotic nuclear receptor
    Changcheng Zhou
    Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA
    Mol Pharmacol 71:220-9. 2007
    ..g., lack of efficacy), which are a major public health problem, this discovery could lead to the development of important new therapeutic and dietary approaches to reduce the frequency of undesirable inducer-drug interactions...
  6. pmc Modulation of aflatoxin B1-mediated genotoxicity in primary cultures of human hepatocytes by diindolylmethane, curcumin, and xanthohumols
    Kerstin Gross-Steinmeyer
    Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105, USA
    Toxicol Sci 112:303-10. 2009
    ..The increase in DNA damage by DIM raises potential safety risks for dietary supplements of DIM and its precursor indole-3-carbinol...