Molecular mechanisms of etomoxir-induced toxicity

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dc.contributor.advisor Richard T. Miller, Committee Member en_US
dc.contributor.advisor Talmage T. Brown, Committee Co-Chair en_US
dc.contributor.advisor Kevin T. Morgan, Committee Co-Chair en_US
dc.contributor.advisor Tony R. Fox, Committee Member en_US
dc.contributor.advisor Philip L. Sannes, Committee Member en_US
dc.contributor.author Merrill, Christine Lee en_US
dc.date.accessioned 2010-04-02T18:28:16Z
dc.date.available 2010-04-02T18:28:16Z
dc.date.issued 2002-12-16 en_US
dc.identifier.other etd-09062002-134236 en_US
dc.identifier.uri http://www.lib.ncsu.edu/resolver/1840.16/3240
dc.description.abstract Etomoxir (ET) is a member of a family of substituted 2-oxirane-carboxylic acids that inhibit mitochondrial long-chain fatty acid beta-oxidation (FAO), ketogenesis and gluconeogenesis. Once converted to its CoA ester, ET irreversibly binds to the CPT-1 catalytic site and prevents long chain fatty acids from entering the mitochondrion. Along with this inhibition of FAO, ET causes a shift in energy substrate utilization from fatty acids to glucose, leading to systemic hypoglycemia, hypoketonemia, and hypotriglyceridemia. These effects make ET potentially useful in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). The compound has been shown to induce cardiac and hepatic hypertrophy in animals and, therefore, has not been fully developed as an antidiabetic agent to date. It is well established that ET activates the peroxisome proliferator activated receptor-alpha (PPARα) which can cause both oxidative stress and dysregulation of the cell cycle control gene program. The goal of this research was to evaluate the ET-induced alterations in gene expression profiles in hepatocytes to elucidate the possible role of cell growth dysregulation and/or oxidative stress in ET-induced hepatic toxicity. In HepG2 cells treated with a high dose of ET, gene expression strongly suggestive of oxidative stress was observed and this was supported by decreased levels of reduced glutathione, reduced/oxidized glutathione ratio (GSH/GSSG), concurrent increase in oxidized glutathione (GSSG) and superoxide generation. A significant decrease in mitochondrial membrane potential and ATP levels implicated impairment of mitochondrial energy metabolism. Other gene expression findings suggested activation of p53, DNA repair and cell cycle arrest. In rats, ET induced a strong mitogenic response in the livers of rats 24 h after administration of one 25 mg/kg dose, that was consistent with the cell proliferation caused by peroxisome proliferators. This finding was coincident with a predominance of cell proliferation/growth-related gene expression alterations. Oxidative stress genes were down regulated; suggesting that this is not a viable etiologic mechanism for induction of ET-induced hepatic hypertrophy. PPARα appears to play a role in ET-induced hepatic hypertrophy, as shown by the early cell proliferation followed by increased level of PPARA mRNA, peroxisome proliferation and increase of PPARα-related genes. en_US
dc.rights I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. en_US
dc.subject etomoxir en_US
dc.subject liver en_US
dc.subject peroxisome proliferator activated receptor-alpha en_US
dc.subject oxidative stress en_US
dc.title Molecular mechanisms of etomoxir-induced toxicity en_US
dc.degree.name PhD en_US
dc.degree.level dissertation en_US
dc.degree.discipline Comparative Biomedical Sciences en_US


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