Molecular Mechanisms of Hydrogen Sulfide Toxicity

Abstract

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.

High-sulfur in beef cattle diets: A review

“…While H 2 S has gained attention as a potentially important signaling molecule at low concentrations in the body (Li et al, 2009), excessive concentrations of H 2 S can block cytochrome C oxidase, leading to depletion of ATP and ultimately causing cell death (Beauchamp et al, 1984). However, another possible mechanism by which H 2 S induces cytotoxicity is by forming reactive S species and increasing the formation of reactive oxygen species thus causing oxidative damage (Truong et al, 2006). Based on this work (Truong et al, 2006), a proposed model by which H 2 S may cause cellular death is shown in Figure 3.…”

“…However, another possible mechanism by which H 2 S induces cytotoxicity is by forming reactive S species and increasing the formation of reactive oxygen species thus causing oxidative damage (Truong et al, 2006). Based on this work (Truong et al, 2006), a proposed model by which H 2 S may cause cellular death is shown in Figure 3. It is unclear if H 2 S-induced cytotoxicity is the cause of damage to brain cells in cattle experiencing S-PEM.…”

“…High S in the body has been identified as a potential cause in the development of oxidative stress, as evident by a depletion of glutathione (GSH; Truong et al, 2006;Pogge and Hansen, 2013), which may contribute to an oxidative environment postmortem. It is well established that a postmortem oxidative environment interferes with proteolysis thus hindering the tenderization process (Guttmann and Johnson, 1998;Lametsch et al, 2008;Rowe et al, 2004).…”

“…In these studies, S-induced oxidative stress was noted by a decrease in reduced GSH relative to its oxidized form (GSSG) in cultured rat hepatocytes (Truong et al, 2006) or beef liver collected after steers received 0.55% S diets for 143 d (Pogge and Hansen, 2013). In both studies, the depletion of GSH by S suggests the importance of GSH 30 in detoxification of excess S. Depleting GSH may increase strain on other body antioxidants such as vitamin C, vitamin E, and trace mineral-dependent enzymes such as superoxide dismutase, catalase, and glutathione peroxidase; which, under normal conditions are able to neutralize radical species through the donation of electrons.…”

“…Exposure to high concentrations of S, and therefore H 2 S, has been identified as a potential culprit in the generation of oxidative stress both in vitro and in vivo (Truong et al, 2006;Pogge and Hansen, 2013;Figure 3). In these studies, S-induced oxidative stress was noted by a decrease in reduced GSH relative to its oxidized form (GSSG) in cultured rat hepatocytes (Truong et al, 2006) or beef liver collected after steers received 0.55% S diets for 143 d (Pogge and Hansen, 2013).…”