Methyl mercaptan (methanethiol) is a colorless toxic gas that smells like rotten cabbage. It is considered a high priority chemical threat agent by the CounterACT Program, with its toxicity similar in degree to that of hydrogen sulfide, but less than that of hydrogen cyanide. Like hydrogen sulfide and hydrogen cyanide, methyl mercaptan inhibits cytochrome c oxidase, the terminal enzyme of the mitochondrial electron transport chain, and it thus inhibits cellular respiration. Cyanide and sulfide inhibition of cytochrome c oxidase increases cellular production of reactive oxygen species and reduces ATP generation, but whether methyl mercaptan also induces oxidative stress and reduces ATP generation is not known. Methyl mercaptan is released from decaying organic matter, and can be present in coal tar, crude oil, and natural gas. It is used in several industries, for example in manufacturing plastics and pesticides, and as an additive to jet fuel. Seven workers have been killed in the past several years when they were exposed to methyl mercaptan gas in industrial accidents. Unfortunately, no antidote exists for methyl mercaptan poisoning, and treatment consists of general supportive care. A specific antidote is clearly needed, preferably one that can be administered quickly in the field, for example by intramuscular injection or inhalational delivery. Cobinamide, a vitamin B12 analog, binds hydrogen cyanide and hydrogen sulfide?and thereby neutralizes these toxic gases?and rescues animals from cyanide and sulfide poisoning. We have found that cobinamide also binds and neutralizes methyl mercaptan, and rescues mice from methyl mercaptan poisoning. Cobinamide?s rescue of mice is potentiated by sodium thiosulfate, a well- known cyanide antidote that we found reacts directly with methyl mercaptan. We now propose to determine: (i) the mechanism of methyl mercaptan-induced toxicity, specifically studying if methyl mercaptan induces oxidative stress and reduces ATP production and whether cobinamide and thiosulfate reverse these potential effects of methyl mercaptan; (ii) the optimal cobinamide and thiosulfate doses and the optimal ratio of these two agents that rescue mice from a lethal exposure to methyl mercaptan gas; (iii) the cobinamide and thiosulfate doses that rescue rabbits and pigs from methyl mercaptan poisoning, basing the initial doses of the two drugs and their relative ratio on the mouse studies; and (iv) whether inhaled cobinamide and thiosulfate provide better pulmonary protection and improved survival than intramuscular injection of the drugs. These studies would be required by the Food and Drug Administration in anticipation of developing cobinamide and thiosulfate as a treatment for methyl mercaptan poisoning. Having one antidote that could treat hydrogen cyanide, hydrogen sulfide, and methyl mercaptan poisoning would be highly advantageous.
Methyl mercaptan, also known as methanethiol, is a poisonous gas that is a decay product of organic material. It is used in the plastics industry, in pesticides, and as a jet fuel additive, and four workers were killed recently when methyl mercaptan gas was released in an industrial accident in Texas; no treatment is available for methyl mercaptan poisoning, and an antidote is urgently needed. We have found that the vitamin B12 analog cobinamide neutralizes methyl mercaptan and rescues mice from lethal doses of methyl mercaptan; cobinamide?s effect is augmented by sodium thiosulfate, an extraordinarily safe agent, and we now propose to study the combination of these two drugs as an antidote against methyl mercaptan poisoning in mice, rabbits, and pigs.
|Rancourt, Raymond C; Rioux, Jacqueline S; Veress, Livia A et al. (2018) Methyl isocyanate inhalation induces tissue factor-dependent activation of coagulation in rats. Drug Chem Toxicol :1-7|
|McGraw, Matthew D; Dysart, Marilyn M; Hendry-Hofer, Tara B et al. (2018) Bronchiolitis Obliterans and Pulmonary Fibrosis after Sulfur Mustard Inhalation in Rats. Am J Respir Cell Mol Biol 58:696-705|
|Fukuda, Satoshi; Enkhbaatar, Perenlei; Nelson, Christina et al. (2018) Lack of durable protection against cotton smoke-induced acute lung injury in sheep by nebulized single chain urokinase plasminogen activator or tissue plasminogen activator. Clin Transl Med 7:17|
|Idell, Steven; Rahman, Najib M (2018) Intrapleural Fibrinolytic Therapy for Empyema and Pleural Loculation: Knowns and Unknowns. Ann Am Thorac Soc 15:515-517|
|Logue, Brian A; Zhang, Zhiling; Manandhar, Erica et al. (2018) Determination of methyl isopropyl hydantoin from rat erythrocytes by gas-chromatography mass-spectrometry to determine methyl isocyanate dose following inhalation exposure. J Chromatogr B Analyt Technol Biomed Life Sci 1093-1094:119-127|
|Miao, Yusi; Jing, Joseph C; Desai, Vineet et al. (2018) Automated 3D segmentation of methyl isocyanate-exposed rat trachea using an ultra-thin, fully fiber optic optical coherence endoscopic probe. Sci Rep 8:8713|
|Okponyia, Obiefuna C; McGraw, Matthew D; Dysart, Marilyn M et al. (2018) Oxygen Administration Improves Survival but Worsens Cardiopulmonary Functions in Chlorine-exposed Rats. Am J Respir Cell Mol Biol 58:107-116|
|McGraw, Matthew D; Osborne, Christopher M; Mastej, Emily J et al. (2017) Editor's Highlight: Pulmonary Vascular Thrombosis in Rats Exposed to Inhaled Sulfur Mustard. Toxicol Sci 159:461-469|
|Anantharam, Poojya; Whitley, Elizabeth M; Mahama, Belinda et al. (2017) Cobinamide is effective for treatment of hydrogen sulfide-induced neurological sequelae in a mouse model. Ann N Y Acad Sci 1408:61-78|
|Summerhill, Eleanor M; Hoyle, Gary W; Jordt, Sven-Eric et al. (2017) An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness. Ann Am Thorac Soc 14:1060-1072|
Showing the most recent 10 out of 13 publications