Molecular mechanisms of etomoxir-induced toxicity

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Title: Molecular mechanisms of etomoxir-induced toxicity
Author: Merrill, Christine Lee
Advisors: Richard T. Miller, Committee Member
Talmage T. Brown, Committee Co-Chair
Kevin T. Morgan, Committee Co-Chair
Tony R. Fox, Committee Member
Philip L. Sannes, Committee Member
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.
Date: 2002-12-16
Degree: PhD
Discipline: Comparative Biomedical Sciences

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