Nitroaromatic Induced Metabolic Impairment Through Chemical Modification of Alpha-ketoacid Dehydrogenase Complexes

Nitroaromatic Induced Metabolic Impairment Through Chemical Modification of Alpha-ketoacid Dehydrogenase Complexes

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1, 3-Dinitrobenzene (1, 3-DNB) is one of several metabolic disruptors known to induce neuropathology characteristics of acute energy deprivation syndromes (AEDS). AEDS produce focal, glio-vascular lesions in conserved brainstem regions consistent with their high metabolic activity. Dysfunctions in various metabolic pathways are described for many inducers of AEDS, but the molecular targets of 1, 3-dinitrobenzene have not been identified. The regional distribution and severity of the lesions produced by nitroaromatic chemicals closely resembles thiamine deficiency, suggesting that these AEDS potentially share a common defect in energy metabolism mediated by thiamine dependent enzymes. alpha-keto acid dehydrogenase complexes, including the pyruvate dehydrogenase (PDHc) and alpha-ketoglutarate dehydrogenase (KGDHc), are thiamine dependent, multi-component enzyme systems occupying critical sites in energy metabolism. The investigations presented in this thesis were done in order to determine if 1, 3-DNB possesses the capability of directly inhibiting these essential metabolic enzymes, as well as to examine potential mechanisms of this impairment. These studies demonstrate that 1, 3-DNB exposure resulted in rapid and dose-dependent inhibition of purified PDHc. Additionally, the metabolic status in the C6 glioma astrocyte model is compromised by exposure to 1, 3-DNB. This metabolic impairment resulted in significant loss of both PDHc and KGDHc activities. The modification of protein bound lipoic acid, an essential component of these complexes, occurred in both a dose- and time-dependent manner and appears to underlie the dysfunction of this enzyme complex. Potentially, this modification is due to direct oxidation by 1, 3-DNB or one of its highly reactive intermediates and not to induction of oxidative stress. In addition to examining metabolic impairment of astrocytes, proposed pathways of astrocyte-mediated neuronal protection in the early stages of 1, 3-DNB toxicity were investigated. The astrocyte cell model was shown to protect metabolically impaired SY5Y neuroblastomas during 1, 3-DNB exposure. Implications for the role of adenosine-mediated signaling pathways are discussed with respect to this neuroprotection. Further investigations into the complex relationship between astrocytes and neurons during acute energy deprivation are required.... Indianapolis, IN) employing a commercial reagent (LD-L) from Sigma Diagnostics as described in provided manual. ... At the following time points (6, 12, 24, and 36hr), plates were rinsed in D-PBS and immediately snap frozen in liquid N2. ... Isocratic elution was performed on a Symmetry 300TM C-18 column (4.6 x 150 mm, 5 (xm) at a flow rate of 0.6 ml/min and peak absorbance recorded at 206 nm.

Title:Nitroaromatic Induced Metabolic Impairment Through Chemical Modification of Alpha-ketoacid Dehydrogenase Complexes
Author: James Arthur Miller
Publisher:ProQuest - 2008

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