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

Autor: George P. Philipopoulos, John Tat, Adriano Chan, Jingjing Jiang, David Mukai, Tanya Burney, Melody Doosty, Sari Mahon, Hemal H. Patel, Carl W. White, Matthew Brenner, Jangwoen Lee, Gerry R. Boss
Rok vydání: 2022
Předmět:
Zdroj: Clinical toxicology (Philadelphia, Pa.), vol 60, iss 5
Clin Toxicol (Phila)
ISSN: 1556-9519
1556-3650
DOI: 10.1080/15563650.2021.2017949
Popis: 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 (Kd = 84 ��M), 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.
Databáze: OpenAIRE
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