# Cobinamide for acute methylmercaptan inhalation

> **NIH NIH U54** · UNIVERSITY OF COLORADO DENVER · 2020 · $352,389

## Abstract

SUMMARY
Methyl mercaptan (methanethiol) is a colorless toxic gas that smells like rotten cabbage. It is considered a high
priority chemical threat agent by the CounterACT Program, with its toxicity similar in degree to that of hydrogen
sulfide, but less than that of hydrogen cyanide. Like hydrogen sulfide and hydrogen cyanide, methyl mercaptan
inhibits cytochrome c oxidase, the terminal enzyme of the mitochondrial electron transport chain, and it thus
inhibits cellular respiration. Cyanide and sulfide inhibition of cytochrome c oxidase increases cellular production
of reactive oxygen species and reduces ATP generation, but whether methyl mercaptan also induces oxidative
stress and reduces ATP generation is not known. Methyl mercaptan is released from decaying organic matter,
and can be present in coal tar, crude oil, and natural gas. It is used in several industries, for example in
manufacturing plastics and pesticides, and as an additive to jet fuel. Seven workers have been killed in the
past several years when they were exposed to methyl mercaptan gas in industrial accidents. Unfortunately, no
antidote exists for methyl mercaptan poisoning, and treatment consists of general supportive care. A specific
antidote is clearly needed, preferably one that can be administered quickly in the field, for example by
intramuscular injection or inhalational delivery. Cobinamide, a vitamin B12 analog, binds hydrogen cyanide and
hydrogen sulfide—and thereby neutralizes these toxic gases—and rescues animals from cyanide and sulfide
poisoning. We have found that cobinamide also binds and neutralizes methyl mercaptan, and rescues mice
from methyl mercaptan poisoning. Cobinamide’s rescue of mice is potentiated by sodium thiosulfate, a well-
known cyanide antidote that we found reacts directly with methyl mercaptan. We now propose to determine: (i)
the mechanism of methyl mercaptan-induced toxicity, specifically studying if methyl mercaptan induces
oxidative stress and reduces ATP production and whether cobinamide and thiosulfate reverse these potential
effects of methyl mercaptan; (ii) the optimal cobinamide and thiosulfate doses and the optimal ratio of these
two agents that rescue mice from a lethal exposure to methyl mercaptan gas; (iii) the cobinamide and
thiosulfate doses that rescue rabbits and pigs from methyl mercaptan poisoning, basing the initial doses of the
two drugs and their relative ratio on the mouse studies; and (iv) whether inhaled cobinamide and thiosulfate
provide better pulmonary protection and improved survival than intramuscular injection of the drugs. These
studies would be required by the Food and Drug Administration in anticipation of developing cobinamide and
thiosulfate as a treatment for methyl mercaptan poisoning. Having one antidote that could treat hydrogen
cyanide, hydrogen sulfide, and methyl mercaptan poisoning would be highly advantageous.

## Key facts

- **NIH application ID:** 10003336
- **Project number:** 5U54ES027698-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** GERRY R BOSS
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,389
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003336

## Citation

> US National Institutes of Health, RePORTER application 10003336, Cobinamide for acute methylmercaptan inhalation (5U54ES027698-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10003336. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*