The investigators have recently discovered that cells, organs and organisms can be protected against the toxic effects of a variety of chemicals with the administration of alpha-tocopheryl succinate (TS). TS-mediated protection appears to result not from the cellular accumulation of alpha-tocopherol, as previously suggested, but rather from succinate released from cellular TS. The applicants suggest that TS serves as a lipophilic carrier for succinate, thereby promoting cellular energy production and cytoprotection against chemical toxicity. The objective of the proposed research is to define the protective role of TS in carbon tetrachloride-and ethyl methanesulfonate-induced toxicity. The working hypothesis is that the cellular release of succinate from TS promotes cellular energy production, enabling the maintenance of essential cellular process and cellular viability during a toxic chemical insult. This hypothesis will be tested in vitro (rat hepatocytes) and in vivo using the toxic chemicals, carbon tetrachloride and ethyl methanesulfonate, by: determining the TS dosing conditions required for optimal protection against chemical toxicity; determining the portion of the TS molecule that is responsible for cytoprotection against chemical toxicity; determining the metabolic fate and tissue and subcellular distribution of administered TS; and determining the molecular mechanism of TS-mediated cytoprotection against chemical toxicity.
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