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Methyl mercaptan (CH 3 SH) is a colorless, toxic gas with potential for occupational exposure and used as a weapon of mass destruction. Inhalation at high concentrations can result in dyspnea, hypoventilation, seizures, and death. No specific methyl mercaptan antidote exists, highlighting a critical need for such an agent. Here, we investigated the mechanism of CH 3 SH toxicity, and rescue from CH 3 SH poisoning by the vitamin B 12  analog cobinamide, in mammalian cells. We also developed lethal CH 3 SH inhalation models in mice and rabbits, and tested the efficacy of intramuscular injection of cobinamide as a CH 3 SH antidote. We found that cobinamide binds to CH 3 SH ( Kd  = 84 µM), and improved growth of cells exposed to CH 3 SH. CH 3 SH reduced cellular oxygen consumption and intracellular ATP content and activated the stress protein c-Jun N-terminal kinase (JNK); cobinamide reversed these changes. A single intramuscular injection of cobinamide (20 mg/kg) rescued 6 of 6 mice exposed to a lethal dose of CH 3 SH gas, while all six saline-treated mice died ( p  = 0.0013). In rabbits exposed to CH 3 SH gas, 11 of 12 animals (92%) treated with two intramuscular injections of cobinamide (50 mg/kg each) survived, while only 2 of 12 animals (17%) treated with saline survived ( p  = 0.001). We conclude that cobinamide could potentially serve as a CH 3 SH antidote.

Methyl mercaptan gas: mechanisms of toxicity and demonstration of the effectiveness of cobinamide as an antidote in mice and rabbits