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.

A Novel, Direct NO Donor Regulates Osteoblast and Osteoclast Functions and Increases Bone Mass in Ovariectomized Mice

“…10, 30, 32 Here, we examined the skeletal effects of a novel NO donor, nitrosyl-cobinamide (NO-Cbi), derived from the vitamin B 12 precursor cobinamide; it releases NO directly, without biotransformation or generation of reactive oxygen species. 33–36 We found that NO-Cbi enhanced trabecular bone mass in intact and OVX mice by enhancing osteoblast activity and inhibiting osteoclast differentiation.…”

“…Boss et al, unpublished data and 33 ). After NO release, cobinamide is generated, and cobinamide can bind O 2 − and other reactive oxygen species, 36 providing a potential added benefit of protecting cells from oxidative stress. Repeated administration of NO-Cbi does not induce tolerance, and NO-Cbi is stable and can be administered by multiple routes, including oral ingestion (G.R.…”

Characterizing a mouse model for evaluation of countermeasures against hydrogen sulfide–induced neurotoxicity and neurological sequelae

“…Only one in three surviving rats that received a higher dose demonstrated frank lesions 1 week after exposure . In an inhalation mouse model using anesthetized mice, the focus of the study was biochemical changes, and neurodegeneration was not evaluated . None of these alternative models examined sex differences in rats or mice.…”

Environmental toxicology of hydrogen sulfide

“…Since the details of these interactions in physiological circumstances are still emerging, any associated pathological biochemistry is even less well delineated, but there is promising scope here for the discovery of a mechanism to explain H 2 S-induced pulmonary edema and, thus, potential therapeutic targets. There has been some recent focus on the lung epithelial sodium channel as a target for treating H 2 S-induced acute pulmonary edema [178–180]. Unfortunately, there is cause for pessimism with regard to this suggestion because multicenter clinical trials with epithelial sodium channel activators/stimulators for the treatment of patients with pulmonary edema have, thus far, proven disappointing [181].…”