Methyl mercaptan gas: mechanisms of toxicity and demonstration of the effectiveness of cobinamide as an antidote in mice and rabbits. (4th May 2022)

• Record Type: Journal Article
• Authors: Philipopoulos, George P.; Tat, John; Chan, Adriano; Jiang, Jingjing; Mukai, David; Burney, Tanya; Doosty, Melody; Mahon, Sari; Patel, Hemal H.; White, Carl W.; Brenner, Matthew; Lee, Jangwoen; Boss, Gerry R.
• Is Part Of: Clinical toxicology. Volume 60:Number 5(2022)
• Page Start: 615
• Page End: 622
• Publication Date: 2022-05-04
• Subjects: Methyl mercaptan -- cobinamide -- rescue; Toxicology -- Periodicals; Toxicological emergencies -- Periodicals; 615.9
• DOI: 10.1080/15563650.2021.2017949
• Languages: English
• ISSNs: 1556-3650

Abstract

Abstract: Context: Methyl mercaptan (CH3 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 CH3 SH toxicity, and rescue from CH3 SH poisoning by the vitamin B12 analog cobinamide, in mammalian cells. We also developed lethal CH3 SH inhalation models in mice and rabbits, and tested the efficacy of intramuscular injection of cobinamide as a CH3 SH antidote. Results: We found that cobinamide binds to CH3 SH ( K d = 84 µM), and improved growth of cells exposed to CH3 SH. CH3 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 CH3 SH gas, while all six saline-treated mice died ( p = 0.0013). In rabbits exposed to CH3 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 CH3 SH antidote.