Abstract
CONTEXT: 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. RESULTS: We found that cobinamide binds to CH(3)SH (K(d) = 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). CONCLUSION: We conclude that cobinamide could potentially serve as a CH(3)SH antidote.