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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antidotes / pharmacology*
  • Apoptosis
  • Brain / drug effects
  • Brain / metabolism
  • Cell Differentiation
  • Cobamides / pharmacology*
  • Drosophila melanogaster
  • Electron Transport Complex IV / metabolism
  • F2-Isoprostanes / antagonists & inhibitors
  • F2-Isoprostanes / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Hydrogen Sulfide / antagonists & inhibitors
  • Hydrogen Sulfide / toxicity*
  • Hydroxyl Radical / antagonists & inhibitors
  • Hydroxyl Radical / metabolism
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Heart / drug effects
  • Mitochondria, Heart / metabolism
  • Myocardium / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oxidative Stress
  • Potassium Cyanide / antagonists & inhibitors
  • Potassium Cyanide / toxicity*
  • Rats
  • Sulfides / antagonists & inhibitors
  • Sulfides / toxicity*

Substances

  • Antidotes
  • Cobamides
  • F2-Isoprostanes
  • Sulfides
  • cobinamide
  • Hydroxyl Radical
  • Electron Transport Complex IV
  • sodium bisulfide
  • Potassium Cyanide
  • Hydrogen Sulfide