INHIBITION OF PARAQUAT OXYGEN-MEDIATED TOXICITY

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It is proposed that the effects of methylene blue and thionin on paraquat toxicity be investigated using rats as the experimental model. Paraquat produces its toxic effects by oxygen-radical production, NADPH depletion, and mixed disulfide production. Methylene blue and thionin are known to stimulate NADPH production and preliminary experiments show they will replace oxygen as electron carriers and also react with oxygen radicals. By replacing oxygen as the electron carrier, methylene blue and thionin should prevent the formation of oxygen or paraquat radicals. Previous attempts to reduce paraquat toxicity used agents that worked by removing the radicals after their formation. Information derived from this project would also be used to investigate other environmental toxins (lead, aromatic-nitrate solvents) that may produce oxygen radicals at a slower rate. The principal investigator is interested in a career in environmental toxicology with research emphasis on biochemical changes in anti-oxidant enzyme systems from environmental chemicals. The above project will enable the investigator to study a well defined oxygen-radical producing system and interaction with anti-oxidant enzyme systems. By introducing a change in the system (methylene blue or thionin) an original contribution to scientific knowledge may also be made. The award would enable the investigator to devote full time to environmental toxicology (80% research, 20% clinical or teaching) by removing all other duties or responsibilities. The University of California, San Diego has excellent research and clinical facilities for studying environmental toxicology. There is a clinical occupational health group at the University of California, San Diego-Medical Center and an environmental toxicology program at the San Diego Zoo. In addition, the University's close proximity to Mexico provides unique exposure to environmental problems not found in the United States. The principal investigator will be able to participate in both of the above programs. It is anticipated that the principal investigator, following completion of the program, will join the Department of Pathology at the University of California, San Diego as an Assistant Professor with research, teaching, and clinical responsibilities in environmental toxicology.