A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase.

摘要: Exposure of Neuro-2a and PC12 cells to micromolar concentrations sulfite caused an increase in reactive oxygen species a decrease ATP. Likewise, the biosynthesis ATP intact rat brain mitochondria from oxidation glutamate was inhibited by sulfite. Glutamate-driven respiration increased mitochondrial membrane potential (MMP), this abolished but MMP generated malate succinate not affected. The rate production NADH exogenous NAD+ added extracts sulfite, preincubated with failed reduce NAD+. Glutamate dehydrogenase (GDH) extract dose-dependently as activity purified enzyme. An Km (glutamate) Vmax resulting attenuation Vmax/Km at 100 microm suggest mixed type inhibition. However, uncompetitive inhibition noted decreases both (NAD+) Vmax, whereas remained relatively constant. We propose that GDH is one target action leading alpha-ketoglutarate diminished flux through tricarboxylic acid cycle accompanied electron transport chain, decreased MMP, synthesis. Because major metabolite brain, could contribute severe phenotype oxidase deficiency human infants.