title: 1,3-Dinitrobenzene-induced metabolic impairment through selective inactivation of the pyruvate dehydrogenase complex.
abstract: Prolonged exposure to the chemical intermediate, 1,3-dinitrobenzene (1,3-DNB), produces neuropathology in the central nervous system of rodents analogous to that observed in various conditions of acute energy deprivation including thiamine deficiency and Leigh's necrotizing encephalopathy. Increased production of reactive intermediates in addition to induction of oxidative stress has been implicated in the neurotoxic mechanism of 1,3-DNB, but a clear metabolic target has not been determined. Here we propose that similar to thiamine deficiency, the effects of 1,3-DNB on metabolic status may be due to inhibition of the thiamine-dependent α-ketoacid dehydrogenase complexes. The effects of 1,3-DNB on astroglial metabolic status and α-ketoacid dehydrogenase activity were evaluated using rat C6 glioma cells. Exposure to 1,3-DNB resulted in altered morphology and biochemical dysfunction consistent with disruption of oxidative energy metabolism. Cotreatment with acetyl-carnitine or acetoacetate attenuated morphological and metabolic effects of 1,3-DNB exposure as well as increased cell viability. 1,3-DNB exposure inhibited pyruvate dehydrogenase complex (PDHc) and the inhibition correlated with the loss of lipoic acid (LA) immunoreactivity, suggesting that modification of LA is a potential mechanism of inhibition. Treatment with antioxidants and thiol-containing compounds failed to protect against loss of LA. Alternatively, inhibition of dihydrolipoamide dehydrogenase, the E3 component of the complex attenuated loss of LA. Collectively, these data suggest that 1,3-DNB impairs oxidative energy metabolism through direct inhibition of the PDHc and that this impairment is due to perturbations in the function of protein-bound LA.
authors.affiliation: Center for Environmental Medicine, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Miller
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Runkle
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Tjalkens
authors.forename: Martin A
authors.initials: MA
authors.lastname: Philbert
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D004136:Dinitrobenzenes / Q000633:toxicity*; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D018384:Oxidative Stress; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D013832:Thiamine Deficiency / Q000097:blood; D008063:Thioctic Acid / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004136:Dinitrobenzenes; D024101:Mitochondrial Proteins; D011768:Pyruvate Dehydrogenase Complex; D008063:Thioctic Acid; C017906:3-dinitrobenzene