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

Methyl mercaptan (CH₃SH) 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 CH₃SH toxicity, and rescue from CH₃SH poisoning by the vitamin B₁₂ analog cobinamide, in mammalian cells. We also developed lethal CH₃SH inhalation models in mice and rabbits, and tested the efficacy of intramuscular injection of cobinamide as a CH₃SH antidote. We found that cobinamide binds to CH₃SH (K_d = 84 µM), and improved growth of cells exposed to CH₃SH. CH₃SH 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 CH₃SH gas, while all six saline-treated mice died (p = 0.0013). In rabbits exposed to CH₃SH 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 CH₃SH antidote. [ABSTRACT FROM AUTHOR]