Nitroaromatic Induced Metabolic Impairment through Chemical Modification of à-Ketoacid Dehydrogenase Complexes.

1;3-Dinitrobenzene;Pyruvate Dehydrogenase Complex;Astrocytes;Health Sciences;Toxicology

Miller, James ArthurRichardson, Rudy J. ;

University of Michigan

关键词: 1;    3-Dinitrobenzene;    Pyruvate Dehydrogenase Complex;    Astrocytes;    Health Sciences;    Toxicology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/58428/jamesam_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

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.α-Keto acid dehydrogenase complexes, including the pyruvate dehydrogenase (PDHc) and α-ketoglutarate dehydrogenase (KGDHc), are thiamine dependent, multi-component enzyme systems occupying critical sites in energy metabolism.The investigations presented in this thesis were performed in order to determine whether or not 1,3-DNB possesses the capability of directly inhibiting these essential metabolic enzymes, and to examine potential mechanisms of this impairment.These studies demonstrated 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 was 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 SH-SY5Y neuroblastomas during 1,3-DNB exposure.Implications for the role of adenosine-mediated signaling pathways are discussed with respect to neuroprotection.Further investigations into the complex relationship between astrocytes and neurons during acute energy deprivation are required.