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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES005452-03
Application #
2154106
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1991-06-01
Project End
1995-03-31
Budget Start
1993-06-01
Budget End
1995-03-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Zhang, J G; Tirmenstein, M A; Nicholls-Grzemski, F A et al. (2001) Mitochondrial electron transport inhibitors cause lipid peroxidation-dependent and -independent cell death: protective role of antioxidants. Arch Biochem Biophys 393:87-96
Tirmenstein, M A; Nicholls-Grzemski, F A; Zhang, J G et al. (2000) Glutathione depletion and the production of reactive oxygen species in isolated hepatocyte suspensions. Chem Biol Interact 127:201-17
Tirmenstein, M A; Nicholls-Grzemski, F A; Schmittgen, T D et al. (2000) Characterization of nitric oxide production following isolation of rat hepatocytes. Toxicol Sci 53:56-62
Tirmenstein, M A; Nicholls-Grzemski, F A; Schmittgen, T D et al. (2000) Glutathione-dependent regulation of nitric oxide production in isolated rat hepatocyte suspensions. Antioxid Redox Signal 2:767-77
Nicholls-Grzemski, F A; Tirmenstein, M A; Fariss, M W (1999) Time-dependent production of nitric oxide by rat hepatocyte suspensions. Biochem Pharmacol 57:1223-6
Tirmenstein, M A; Ge, X; Elkins, C R et al. (1999) Administration of the tris salt of alpha-tocopheryl hemisuccinate inactivates CYP2E1, enhances microsomal alpha-tocopherol levels and protects against carbon tetrachloride-induced hepatotoxicity. Free Radic Biol Med 26:825-35
Tirmenstein, M A; Watson, B W; Haar, N C et al. (1998) Sensitive method for measuring tissue alpha-tocopherol and alpha-tocopheryloxybutyric acid by high-performance liquid chromatography with fluorometric detection. J Chromatogr B Biomed Sci Appl 707:308-11
Tirmenstein, M A; Pierce, C A; Leraas, T L et al. (1998) A fluorescence plate reader assay for monitoring the susceptibility of biological samples to lipid peroxidation. Anal Biochem 265:246-52
Fariss, M W; Lippman, H R; Mumaw, V R et al. (1997) Cholesteryl hemisuccinate treatment protects rodents from the toxic effects of acetaminophen, adriamycin, carbon tetrachloride, chloroform and galactosamine. Toxicol Lett 90:133-44
Tirmenstein, M A; Leraas, T L; Fariss, M W (1997) alpha-Tocopheryl hemisuccinate administration increases rat liver subcellular alpha-tocopherol levels and protects against carbon tetrachloride-induced hepatotoxicity. Toxicol Lett 92:67-77

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