title: Molecular mechanisms of hydrogen sulfide toxicity.
abstract: BACKGROUND
  The toxicity of H2S has been attributed to its ability to inhibit cytochrome c oxidase in a similar manner to HCN. However, the successful use of methemoglobin for the treatment of HCN poisoning was not successful for H2S poisonings even though the ferric heme group of methemoglobin scavenges H2S. Thus, we speculated that other mechanisms contribute to H2S induced cytotoxicity. Experimental procedure. Hepatocyte isolation and viability and enzyme activities were measured as described by Moldeus et al. (1978), and Steen et al. (2001).
  
  
  RESULTS
  Incubation of isolated hepatocytes with NaHS solutions (a H2S source) resulted in glutathione (GSH) depletion. Moreover, GSH depletion was also observed in TRIS-HCl buffer (pH 6.0) treated with NaHS. Several ferric chelators (desferoxamime and DETAPAC) and antioxidant enzymes (superoxide dismutase [SOD] and catalase) prevented cell-free and hepatocyte GSH depletion. GSH-depleted hepatocytes were very susceptible to NaHS cytotoxicity, indicating that GSH detoxified NaHS or H2S in cells. Cytotoxicity was also partly prevented by desferoxamine and DETAPC, but it was increased by ferric EDTA or EDTA. Cell-free oxygen consumption experiments in TRIS-HCl buffer showed that NaHS autoxidation formed hydrogen peroxide and was prevented by DETAPC but increased by EDTA. We hypothesize that H2S can reduce intracellular bound ferric iron to form unbound ferrous iron, which activates iron. Additionally, H2S can increase the hepatocyte formation of reactive oxygen species (ROS) (known to occur with electron transport chain). H2S cytotoxicity therefore also involves a reactive sulfur species, which depletes GSH and activates oxygen to form ROS.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Don H
authors.initials: DH
authors.lastname: Truong
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Eghbal
authors.forename: Wayne
authors.initials: W
authors.lastname: Hindmarsh
authors.forename: Sheldon H
authors.initials: SH
authors.lastname: Roth
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Brien
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D004492:Edetic Acid / Q000494:pharmacology; D005290:Ferric Compounds / Q000378:metabolism; D005296:Ferrous Compounds / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000633:toxicity*; D066298:In Vitro Techniques; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000393:Air Pollutants; D005290:Ferric Compounds; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D017382:Reactive Oxygen Species; D004492:Edetic Acid; D005978:Glutathione; D006862:Hydrogen Sulfide