title: Hydrogen Sulfide--Mechanisms of Toxicity and Development of an Antidote.
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.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Adriano
authors.initials: A
authors.lastname: Chan
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.|Center for Aging and Associated Diseases, Helmy Institute of Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
authors.forename: Sameh
authors.initials: S
authors.lastname: Ali
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Saha
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California, USA.
authors.forename: Kristofer J
authors.initials: KJ
authors.lastname: Haushalter
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Wai-Ling Macrina
authors.initials: WL
authors.lastname: Lam
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Glasheen
authors.affiliation: Neurodegenerative Disease Center, The Scintillon Institute, San Diego, California, USA.
authors.forename: James
authors.initials: J
authors.lastname: Parker
authors.affiliation: Beckman Laser Institute, University of California Irvine, Irvine, California, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brenner
authors.affiliation: Beckman Laser Institute, University of California Irvine, Irvine, California, USA.
authors.forename: Sari B
authors.initials: SB
authors.lastname: Mahon
authors.affiliation: Department of Anesthesiology, University of California San Diego, La Jolla, California, USA.|VA San Diego Healthcare System, San Diego, California, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Patel
authors.affiliation: Neurodegenerative Disease Center, The Scintillon Institute, San Diego, California, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ambasudhan
authors.affiliation: Neurodegenerative Disease Center, The Scintillon Institute, San Diego, California, USA.|Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Renate B
authors.initials: RB
authors.lastname: Pilz
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Boss
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation; D003038:Cobamides / Q000494:pharmacology*; D004331:Drosophila melanogaster; D003576:Electron Transport Complex IV / Q000378:metabolism; D028441:F2-Isoprostanes / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006862:Hydrogen Sulfide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D017665:Hydroxyl Radical / Q000037:antagonists & inhibitors / Q000378:metabolism; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D011190:Potassium Cyanide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D013440:Sulfides / Q000037:antagonists & inhibitors / Q000633:toxicity*
chemical_list: D000931:Antidotes; D003038:Cobamides; D028441:F2-Isoprostanes; D013440:Sulfides; C017142:cobinamide; D017665:Hydroxyl Radical; D003576:Electron Transport Complex IV; C025451:sodium bisulfide; D011190:Potassium Cyanide; D006862:Hydrogen Sulfide