L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

被引:19
作者
Amonpatumrat, Sirirat [2 ,4 ]
Sakurai, Hiroyuki [2 ]
Wiriyasermkul, Pattama [1 ,2 ]
Khunweeraphong, Narakorn [1 ,2 ]
Nagamori, Shushi [1 ]
Tanaka, Hidekazu [1 ]
Piyachaturawat, Pawinee [3 ,4 ]
Kanai, Yoshikatsu [1 ]
机构
[1] Osaka Univ, Grad Sch Med, Dept Pharmacol, Div Biosyst Pharmacol, Suita, Osaka 5650871, Japan
[2] Kyorin Univ, Sch Med, Dept Pharmacol & Toxicol, Tokyo 1818611, Japan
[3] Mahidol Univ, Fac Sci, Dept Physiol, Bangkok 10400, Thailand
[4] Mahidol Univ, Toxicol Grad Program, Bangkok 10400, Thailand
基金
日本学术振兴会;
关键词
methylmercury; L-glutamate; cytotoxicity; apoptosis; oxidative stress;
D O I
10.1254/jphs.08118FP
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Methylmercury (MeHg) is a well-known environmental toxicant. With its lipophilic nature and high reactivity to sulfhydrl groups, it is widely distributed and accumulated in the body to damage cells. Oxidative stress is proposed as a major mechanism underlying the cytotoxic action of MeHg. In the present study, we found that L-glutamate (L-Glu) concentration-dependently increased MeHg cytotoxicity in HeLa S3 cells. The enhancement of the toxicity was accompanied by enhanced apoptosis, increased production of reactive oxygen species, and decreased glutathione level. An anti-oxidant N-acetylcysteine largely alleviated the cytotoxicity, suggesting enhanced oxidative stress behind L-Glu-elicited increase of MeHg toxicity. The effect was specific to L-Glu and L-alpha-aminoadipate, whereas D-Glu, L-aspartate, and D-aspartate were not effective. In addition, the cystine uptake by the cells was mostly mediated by a L-Glu/L-alpha-aminoadipate-sensitive amino acid transport system x(-)c. All these results suggest that the inhibition of system x(-)c by L-Glu underlies the enhancement of MeHg cytotoxicity. The enhancement was highly synergistic because MeHg and L-Glu alone had little toxic effect in the conditions used. This synergism was confirmed in neural cells (neuroblastoma cell lines). It is proposed that similar mechanisms may underlie the neural toxicity of MeHg, particularly in the locality of lesions characteristic of MeHg toxicity.
引用
收藏
页码:280 / 289
页数:10
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