Detoxification of Methylmercury by Hydrogen Sulfide-Producing Enzyme in Mammalian Cells

Yoshida, Eiko; Toyama, Takashi; Shinkai, Yasuhiro; Sawa, Tomohiro; Akaike, Takaaki; Kumagai, Yoshito

doi:10.1021/tx200394g

Cited by 73 publications

(68 citation statements)

References 11 publications

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“…Taken together, the results suggest that RSS derived particularly from CSE play critical roles in regulating activation of the cellular signaling pathway by cadmium and in protecting against cadmium toxicity, presumably via the inactivation of cadmium within the cells. We have previously found that MeHg reacts with RSS to form the detoxified metabolite (MeHg) 2 S (Abiko et al, 2015;Yoshida et al, 2011). Sulfur adducts formed with cadmium have yet to be identified, but we speculate that RSS can trap cadmium to form inert sulfur adducts, protecting cells from cadmium injury.…”

Section: Discussionmentioning

confidence: 90%

“…RSS have strongly nucleophilic properties compared with the parent nucleophiles, so it is likely that RSS will readily trap environmental electrophiles, forming sulfur adducts of the electrophiles. Consistent with this, MeHg reacts with RSS (eg, hydrogen sulfide, GSSH, GSSSG) forming bismethylmercury sulfide, which is not electrophilic and is not very toxic (Abiko et al, 2015;Yoshida et al, 2011). We therefore hypothesized that RSS will modulate the cadmiummediated activation of redox signal transduction pathways such as the HSP/HSF1 pathway and modulate cadmiuminduced cytotoxicity by capturing cadmium.…”

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confidence: 88%

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Cadmium-mediated activation of the HSP90/HSF1 pathway regulated by reactive persulfides/polysulfides

Shinkai

Masuda

Akiyama³

et al. 2017

Toxicol. Sci.

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Cadmium is an environmental electrophile that modifies reactive thiols in proteins, indicating that this heavy metal may modulate redox-signal transduction pathways. The current consensus is that reactive persulfides and polysulfides produced by cystathionine c-lyase (CSE) and cystathionine b-synthase are highly nucleophilic and thus cadmium may be captured by these reactive sulfur species. It has previously been found that electrophile-mediated covalent modifications of the heat shock protein (HSP) are involved in the activation of heat shock factor 1 (HSF1) pathway. The effects of cadmium on the activation of HSP/HSF1 pathway were investigated in this study. Exposure of bovine aortic endothelial cells to cadmium resulted in modification of HSP90 and HSF1 activation, thereby up-regulating the downstream protein HSP70. The siRNA-mediated knockdown of HSF1 enhanced the cytotoxicity induced by cadmium, suggesting that the HSP90/HSF1 pathway contributes to protection against cadmium toxicity. The knockdown of CSE and/or cystathionine b-synthase decreased the levels of reactive sulfur species in the cells and increased the degree of HSP70 induction and cytotoxicity caused by exposure to cadmium. Overexpression of CSE diminished cadmium-mediated up-regulation of HSP70 and cytotoxicity. These results suggest that cadmium activates HSF1 by modifying HSP90 and that reactive sulfur species regulate the redox signal transduction pathway presumably via capture of cadmium, resulting in protection against cadmium toxicity under toxic conditions.

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Section: Discussionmentioning

confidence: 90%

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confidence: 88%

Cadmium-mediated activation of the HSP90/HSF1 pathway regulated by reactive persulfides/polysulfides

Shinkai

Masuda

Akiyama³

et al. 2017

Toxicol. Sci.

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“…In contrast, (MeHg) 2 S itself was not toxic to mice when injected intraperitoneally. 12 Taken together, it seems likely that the capture of MeHg by reactive sulfide derivatives formed endogenously to produce (MeHg) 2 S plays a key role in detoxifying MeHg. While GSH is abundant (>1 mM) in a range of tissues, it has a pKa of 9.12 which indicates that the free anionic GS − is a minority species at physiological pH.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Indeed, we found that MeHg interacts with sodium hydrogen sulfide (NaHS) to produce bismethylmercury sulfide (MeHg) 2 S in in vitro experiments and that (MeHg) 2 S is formed in MeHg-treated SH-SY5Y cells and liver extracts of rats intraperitoneally injected with MeHg. 12 There are numerous sulfur-containing low-molecular-weight compounds in the body, including cysteine (CysSH), cystine (CysSSCys), GSH, glutathione disulfide (GSSG), methionine (Met), and sulfate ions (SO 4 2− ). 13 We recently found that some persulfide species in mammalian cells and tissues such as Cys persulfide (CysSSH), Cys polysulfides (CysSS n SH), GSH persulfide (GSSH), and GSH polysulfides (GSS n SH) contain highly reactive nucleophilic sulfur groups and have antioxidant activities.…”

Section: ■ Introductionmentioning

confidence: 99%

Involvement of Reactive Persulfides in Biological Bismethylmercury Sulfide Formation

Abiko

Yoshida

Ishii

et al. 2015

Chem. Res. Toxicol.

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Bismethylmercury sulfide (MeHg)2S has been found to be a detoxified metabolite of methylmercury (MeHg) that is produced by SH-SY5Y cells and in livers of rats exposed to MeHg. (MeHg)2S could be formed through the interactions between MeHg and sulfur species such as hydrogen sulfide (H2S or HS(-)), but the origin of its sulfur has not been fully identified. We herein examined the formation of (MeHg)2S through interactions between MeHg and persulfides, polysulfides, and protein preparations. Investigations using HPLC/atomic absorption spectrophotometry and EI-MS revealed that NaHS and Na2S4 react readily with MeHg to give (MeHg)2S, and similar results were found using GSH persulfide (GSSH) formed endogenously or generated enzymatically in vitro. (MeHg)2S was also formed by incubation of MeHg with liver and heart cytosolic fractions prepared from wild-type mice but not with those from mice lacking cystathionine γ-lyase (CSE) that catalyzes the formation of cysteine persulfide. Consistent with this, (MeHg)2S was detected in a variety of tissues taken from wild-type mice intraperitoneally injected with MeHg in vivo but not in those from MeHg-injected CSE knockout mice. By separating liver fractions by column chromatography, we found numerous proteins that contain persulfides: one of the proteins was identified as being glutathione S-transferase pi 1. These results indicate that the formation of (MeHg)2S can be attributed to interactions between MeHg and endogenous free persulfide species, as well as protein-bound cysteine persulfide.

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“…Intracellular factors that contribute in reducing MeHg toxicity [i.e., transcription factors such as nuclear factor-E2-related factor 2 (Nrf2) 11) and heat shock factor protein 1 (Hsf1) 12) as well as in vivo metabolites such as hydrogen sulfide (H 2 S) 13) ] have been identified. This proved the existence of novel biological defense mechanisms against MeHg toxicity.…”

Section: Introductionmentioning

confidence: 99%

Role of Intracellular Defense Factors against Methylmercury Toxicity

Hwang

2012

Biological & Pharmaceutical Bulletin

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Methylmercury (MeHg) is a causative agent of Minamata disease and an environmental pollutant that comprises a large portion of organically occurring mercury. Many aspects of the biological defense mechanisms against MeHg toxicity remain unclear. Recently, nuclear factor-E2-related factor 2 (Nrf2), heat shock factor protein 1 (Hsf1), and hydrogen sulfide were identified as intracellular defense factors against MeHg toxicity. These findings suggest that novel biological defense mechanisms against MeHg toxicity exist in the living organism. In addition, the expression of downstream genes that mediate activation of the transcription factors Nrf2 and Hsf1 was markedly induced by MeHg treatment, suggesting that this action is involved in the reduction of MeHg toxicity. On the other hand, when the gaseous form of hydrogen sulfide (H 2 S) binds directly to MeHg, bismethylmercury sulfide (MeHg-S-HgMe) as a low toxicity metabolite is formed. This suggests the involvement of the gaseous form of H 2 S in the reduction of MeHg toxicity. In this topic, we summarize the roles of factors involved in novel biological defense mechanisms against MeHg toxicity.

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Detoxification of Methylmercury by Hydrogen Sulfide-Producing Enzyme in Mammalian Cells

Cited by 73 publications

References 11 publications

Cadmium-mediated activation of the HSP90/HSF1 pathway regulated by reactive persulfides/polysulfides

Cadmium-mediated activation of the HSP90/HSF1 pathway regulated by reactive persulfides/polysulfides

Involvement of Reactive Persulfides in Biological Bismethylmercury Sulfide Formation

Role of Intracellular Defense Factors against Methylmercury Toxicity

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