L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

Amonpatumrat, Sirirat; Sakurai, Hiroyuki; Wiriyasermkul, Pattama; Khunweeraphong, Narakorn; Nagamori, Shushi; Tanaka, Hidekazu; Piyachaturawat, Pawinee; Kanai, Yoshikatsu

doi:10.1254/jphs.08118fp

Cited by 24 publications

(15 citation statements)

References 31 publications

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“…The GSH antioxidant system is the major defense against oxidative damage in the CNS and a direct relationship between the GSH redox system and MeHg neurotoxicity has been proposed (Ballatori and Clarkson, 1982; Shanker et al, 2005; Franco et al, 2006; Amonpatumrat et al, 2008; Stringari et al, 2008; Ni et al, 2011). Herein, the four studied mercurials significantly reduced intracellular GSH levels (when added at concentrations approximating their respective EC 50 ).…”

Section: Discussionmentioning

confidence: 99%

Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake

et al. 2013

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Various forms of mercury possess different rates of absorption, metabolism and excretion, and consequently, toxicity. Methylmercury (MeHg) is a highly neurotoxic organic mercurial. Human exposure is mostly due to ingestion of contaminated fish. Ethylmercury (EtHg), another organic mercury compound, has received significant toxicological attention due to its presence in thimerosal-containing vaccines. This study was designed to compare the toxicities induced by MeHg and EtHg, as well as by their complexes with cysteine (MeHg-S-Cys and EtHg-S-Cys) in the C6 rat glioma cell line. MeHg and EtHg caused significant (p < 0.0001) decreases in cellular viability when cells were treated during 30 min with each mercurial following by a washing period of 24 h (EC50 values of 4.83 and 5.05 μM, respectively). Significant cytotoxicity (p < 0.0001) was also observed when cells were treated under the same conditions with MeHg-S-Cys and EtHg-S-Cys, but the respective EC50 values were significantly increased (11.2 and 9.37 μM). L-Methionine, a substrate for the L-type neutral amino acid carrier transport (LAT) system, significantly protected against the toxicities induced by both complexes (MeHg-S-Cys and EtHg-S-Cys). However, no protective effects of L-methionine were observed against MeHg and EtHg toxicities. Corroborating these findings, L-methionine significantly decreased mercurial uptake when cells were exposed to MeHg-S-Cys (p = 0.028) and EtHg-S-Cys (p = 0.023), but not to MeHg and EtHg. These results indicate that the uptake of MeHg-S-Cys and EtHg-S-Cys into C6 cells is mediated, at least in part, through the LAT system, but MeHg and EtHg enter C6 cells by mechanisms other than LAT system.

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Section: Discussionmentioning

confidence: 99%

Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake

et al. 2013

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“…This interaction decreases the levels of GSH and, consequently, the GSH:GSSG ratio, which contributes to the occurrence of oxidative stress. Accordingly, decreased GSH levels have been reported after MeHg exposure under several in vitro conditions (Kaur et al, 2006; Franco et al, 2007; Amonpatumrat, 2008; Ni et al, 2011). Moreover, in vivo studies with mice have also reported decreased GSH levels in the CNS after MeHg exposure (Franco et al, 2006; Stringari et al, 2008).…”

Section: - Oxidative Hallmarks In Mehg-induced Neurotoxicitymentioning

confidence: 99%

Oxidative stress in MeHg-induced neurotoxicity

Farina¹,

Aschner²,

Rocha³

2011

Toxicology and Applied Pharmacology

285

198

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Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically studied agents.

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“…Here, we provide further evidence that high glucose-induced induced increase of LPO formation leads to the stimulation of glutamate uptake, which may be associated with the apoptosis of pancreatic β-cells. There is a possibility that the high glucose-induced stimulation of glutamate uptake triggers the increase of oxidative stress, since L glutamate enhances cell toxicity via the increase of oxidative stress [29]. It is speculated that mechanisms other than oxidative stress could have a role in the glucose-induced stimulation of glutamate uptake.…”

Section: Discussionmentioning

confidence: 99%

High glucose stimulates glutamate uptakes in pancreatic β-cells

Han

Park

2011

Lab Anim Res

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Pancreatic β-cells are major cells responsible for glucose metabolism in the body. Hyperglycemia is known to be a primary factor in the induction of diabetes mellitus. Glutamate is also an excitatory neurotransmitter in diverse organs. Oxidative stress also plays a pivotal role in the development of diabetes mellitus. However, the effect of hyperglycemia in glutamate uptake in the pancreas is not clear. Furthermore, the relationship between high glucose-induced glutamate uptake and oxidative stress has not been investigated. Therefore, this study was conducted to investigate the effect of high glucose on glutamate uptake in pancreatic β-cells. In the present study, 25 mM glucose stimulated the glutamate uptake in HIT-15 cells of hamster pancreatic β-cells. The treatment of 25 mM glucose and 1 mM glutamate also decreased the cell viability in HIT-15 cells. In addition, the treatment of 25 mM glucose induced an increase of lipid peroxide formation. High glucose-induced increase of LPO formation was prevented by the treatment of antioxidants such as N-acetyl-L-cysteine and quercetin. Furthermore, high glucose-induced stimulation of glutamate uptake and decrease of cell viability were also blocked by the treatment of N-acetyl-L-cysteine and quercetin. In conclusion, high glucose stimulated glutamate uptake via oxidative stress in pancreatic β-cells.

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L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

Cited by 24 publications

References 31 publications

Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake

Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake

Oxidative stress in MeHg-induced neurotoxicity

High glucose stimulates glutamate uptakes in pancreatic β-cells

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