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

Abstract

Context

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.

Results

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).

Conclusion

We conclude that cobinamide could potentially serve as a CH₃SH antidote.

Keywords:

• Methyl mercaptan
• cobinamide
• rescue

Acknowledgements

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Research reported in this publication was supported by the CounterACT program within the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health under Award Number 1U54ES027698 to CWW, with subcontracts to GRB and MB. Approximately $3,360,000, of federal funds supported the effort (100%) on this project. This work was also supported by NIH/NIGMS IRACDA K12 grant GM068524 to JT. No effort on this project was supported by non-federal funds.