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Sci Rep. 2016 Feb 15;6:20831. doi: 10.1038/srep20831.

Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote.

Author information

1
Department of Medicine, University of California San Diego, La Jolla, California, USA.
2
Department of Anesthesiology, University of California San Diego, La Jolla, California, USA.
3
VA San Diego Healthcare System, San Diego, California, USA.
4
Center for Aging and Associated Diseases, Helmy Institute of Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
5
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
6
Neurodegenerative Disease Center, The Scintillon Institute, San Diego, California, USA.
7
Beckman Laser Institute, University of California Irvine, Irvine, California, USA.
8
Department of Neurosciences, University of California San Diego, La Jolla, California, USA.

Abstract

Hydrogen sulfide is a highly toxic gas-second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known, and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F2-isoprostanes in brains and hearts of mice. The vitamin B12 analog cobinamide reversed the cellular toxicity of sulfide, and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues, and that cobinamide has promise as a first specific treatment for sulfide poisoning.

PMID:
26877209
PMCID:
PMC4753484
DOI:
10.1038/srep20831
[Indexed for MEDLINE]
Free PMC Article

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