AuthorHam, Amy-Joan Lorna.
Committee ChairLiebler, Daniel C.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractAntioxidant reactions of vitamin E (α-tocopherol, α-TH) were studied by examining the fate of α-TH during oxidative challenge to isolated rat liver mitochondria and isolated perfused rat liver. The overall goal of this dissertation was to identify the products of antioxidant reactions of α-TH and to determine the relationship between the status of α-TH, lipid peroxidation, and mitochondrial function. In isolated mitochondria, products of α-TH oxidation induced by the radical initiator 2,2'-azobis(2-amidinopropane) dihydrochloride (ABAP) were α-tocopherolquinone (α-TQ), α-tocopherolquinone-2,3-oxide (α-TQE1), and α-tocopherolquinone-5,6-oxide (α-TQE2). ABAP induced lipid peroxidation after 50% of the initial α-TH was depleted and decreased the respiratory control ratio and state 3 and state 4 respiration. In isolated perfused rat liver, the principal products of α-TH oxidation induced by tert-butylhydroperoxide (t-BuOOH) were α-TQ and epoxyquinones α-TQE1/α-TQE2, which were formed from acid-labile 8a-substituted tocopherones and epoxyhydroperoxytocopherones, respectively. t-BuOOH increased gluconeogenesis and decreased ketogenesis, as indicated by increases in lactate and pyruvate and decreases in acetoacetate (AA) and β-hydroxybutyrate β-HBA) in the effluent. In addition, there was a shift to a more oxidized state in mitochondria, as evidenced by a decrease in the β-HBP/AA ratio, a measure of NADH/NAD⁺ ratio in the mitochondria. t-BuOOH increased lipid peroxidation, which was measured by thiobarbituric acid-reactive substances in the effluent and decreased the mitochondrial respiratory control ratio. Dietary supplementation with α-TH increased α-TH levels 7-10 fold, decreased hepatic lipid peroxidation and reversed the mitochondrial uncoupling effects of t-BuOOH, but did not effect changes in metabolism. These studies provide the first comprehensive description of the oxidative turnover of vitamin E in a biological system.
Degree ProgramPharmacology and Toxicology