![]() ![]() Using NaSH, we studied sulfide toxicity in four cell types: hiPSC-derived cortical neurons, primary rat cortical neurons, primary human fibroblasts, and COS-7 monkey kidney cells. Sodium hydrogen sulfide (NaSH) is used commonly as a sulfide source, because it is stable, and much easier to work with than hydrogen sulfide gas 3, 4, 5, 11, 14. Sulfide Inhibits Mitochondrial Respiration Reversal by Cobinamide ![]() ![]() Here we compared mechanisms of sulfide and cyanide toxicity, and found that sulfide generates considerably more oxidative stress than cyanide, and that cobinamide efficiently reverses sulfide toxicity in vitro and in vivo. We have shown it is a far better cyanide antidote than hydroxocobalamin, and recently we found it reacts readily with sulfide, neutralizing two moles of sulfide 29, 30, 31. Sodium nitrite may be beneficial in sulfide-poisoned humans, but only when administered within minutes of exposure 28.Ĭobinamide is the penultimate precursor in hydroxocobalamin (vitamin B 12) biosynthesis by microorganisms ( Supplementary Fig. A sulfide-poisoned person treated with hydroxocobalamin died, but he was moribund when the hydroxocobalamin was given 27. Both agents have shown some benefit in animal models, but both have to be administered either before or immediately after sulfide exposure 15, 25, 26. Two cyanide antidotes-hydroxocobalamin and sodium nitrite-have been tested as sulfide antidotes hydroxocobalamin binds sulfide and nitrite generates both methemoglobin, which binds sulfide, and nitric oxide, which could displace sulfide from cytochrome C oxidase 15, 22, 23, 24. No antidote is currently available for sulfide poisoning and treatment is largely supportive. government considers sulfide a high priority chemical threat, both industrially and as a potential weapon of mass destruction by terrorists its characteristic odor of rotten eggs is lost quickly due to paralysis of olfactory receptors, deceiving people of its presence 1, 2. Sulfide can be generated easily from simple chemicals, which may explain the recent rash of sulfide-induced suicides 20, 21. The number of industrial deaths per year from sulfide is unknown, but sulfide is clearly a major occupational hazard, and even a one-time exposure can lead to long-term neurological deficits 17, 18, 19. Workers are exposed to sulfide in many industries including agriculture, petroleum, and sewage processing, with a third of petroleum workers experiencing some symptoms from sulfide exposure and 8% having become unconscious 1, 15, 16. Sulfide, therefore, has reducing potential-the two-electron redox potential of H 2S is +0.17 V at pH 7-and sulfide’s effect on the cellular redox state is controversial 7, 9, 10, 11, 12, 13, 14. Sulfide could also be expected to induce oxidative stress, but the sulfur in sulfide is in the −2 oxidation state, the most reduced form of sulfur. Cyanide, which also inhibits cytochrome C oxidase, increases mitochondrial generation of superoxide and induces oxidative stress in cells 7, 8. At about 3–30-fold higher concentrations, sulfide becomes toxic by binding to and inhibiting cytochrome C oxidase in complex IV of the electron transport chain, the last complex in the chain prior to ATP synthesis by complex V 3, 4, 5. Sulfide is an endogenous signal transmitter via protein sulfhydration, and, at low intracellular concentrations-0.01 to 1 μM-donates electrons to complex II of the mitochondrial electron transport chain, thereby stimulating ATP production 2, 3, 4, 5, 6. We use the generic term “sulfide” to refer to both species. Hydrogen sulfide (H 2S) is readily water soluble, and, at physiological pH, about two-thirds exists as hydrogen sulfide ion (HS -) and one-third as undissociated H 2S 1. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. ![]() The vitamin B 12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F 2-isoprostanes in brains and hearts of mice. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. Hydrogen sulfide is a highly toxic gas-second only to carbon monoxide as a cause of inhalational deaths. ![]()
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