A Mechanism of Sulfite Neurotoxicity

Abstract

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

Molybdenum in Human Health and Disease

“…SO, which is localized in the mitochondrial intermembrane space oxidizes sulfi te to sulfate, thus no accumulation of sulfi te in the cytosol or extracellular compartments is seen under wild-type conditions [ 67 ]. In MoCD and SOD, sulfi te accumulates fi rst in mitochondria where it has been shown to increase reactive oxygen species [ 149 ]. Sulfi te also decreases ATP synthesis in mitochondria when respiring on glutamate (which is the case in the brain), while using other respiratory substrates such as malate, α-ketoglutarate, and succinate did not show any sulfi te vulnerability [ 149 ].…”

A review of polioencephalomalacia in ruminants: is the development of malacic lesions associated with excess sulfur intake independent of thiamine deficiency?

“…Chiarani et al, [63] found that sulfite increased lipid peroxidation and decreased antioxidant enzyme defences in the rat brain. In addition, when rat and mouse neuronal cells were exposed to sulfite in vitro, there was an increase in the production of ROS and a reduction in intracellular ATP production [65]. The latter authors also found that glutamate dehydrogenase in the rat brain was inhibited by sulfites; hypothesizing that this may result in an energy deficit in the neurons, with secondary inhibition of the citric acid (TCA) cycle [65].…”

“…Sulfite ion is a strong nucleophile and can react with wide variety of biologically important compounds to cause toxicity [63] and the neurotoxic effects of sulfite have been increasingly recognized [63,64]. One electron sulfite oxidation is thought to produce sulfite radicals that have been reported to damage DNA, lipids and proteins [65]. Chiarani et al, [63] found that sulfite increased lipid peroxidation and decreased antioxidant enzyme defences in the rat brain.…”

“…In addition, when rat and mouse neuronal cells were exposed to sulfite in vitro, there was an increase in the production of ROS and a reduction in intracellular ATP production [65]. The latter authors also found that glutamate dehydrogenase in the rat brain was inhibited by sulfites; hypothesizing that this may result in an energy deficit in the neurons, with secondary inhibition of the citric acid (TCA) cycle [65]. The destructive effects of sulfite on thiamine and its functional forms [13,66] may be another mechanism to induce biochemical lesions in the brain (Figure 2).…”

The association of molybdenum cofactor deficiency and pyloric stenosis

“…7,11 NO production can still be achieved through a pathway involving the molybdenum dependent enzyme, xanthine oxidase. 7,13 Review of the literature reported two cases of HPS with MoCD. In-patient with MoCD and SOD, alternative NO production pathway may also be disrupted, predisposing the patient to a reduced level of NO and potentially to pyloric stenosis.…”