L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress
L-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress
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DOI：
10.1254/jphs.08118fp
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发表时间：
2008-11-01
影响因子：
3.5
通讯作者：
Kanai, Yoshikatsu
中科院分区：
文献类型：
--
作者：
Amonpatumrat, Sirirat;Sakurai, Hiroyuki;Kanai, Yoshikatsu
甲基汞(MeHg)是一种著名的环境毒物。由于其亲脂性和对硫氢基的高反应性，它在体内广泛分布和积累，从而损伤细胞。氧化应激被认为是甲基汞细胞毒性作用的主要机制。在本研究中，我们发现L-谷氨酸(L-谷氨酸)呈浓度依赖性地增加甲基汞对HeLaS3细胞的细胞毒性。毒性增强的同时伴随着细胞凋亡的增加、活性氧的产生和谷胱甘肽水平的降低。抗氧化剂N-乙酰半胱氨酸可显著减轻细胞毒性，提示L-谷氨酸诱导的甲基汞毒性增加背后的氧化应激增强。L-谷氨酸和L-α-氨基己二酸特异性起作用，而D-谷氨酸、L-天冬氨酸和D-天冬氨酸无效。此外，细胞对胱氨酸的摄取主要是由L-谷氨酸/L-α-氨基己二酸酯敏感的氨基酸转运系统x(-)c介导的。所有这些结果表明，L-Glu对x(-)c系统的抑制是增强甲基汞细胞毒性的基础。这种增强是高度协同的，因为在所使用的条件下，甲基汞和L-Glu单独使用几乎没有毒性作用。这种协同作用在神经细胞(神经母细胞瘤细胞系)中得到证实。有人认为，类似的机制可能是甲基汞神经毒性的基础，特别是在具有甲基汞毒性特征的损害部位。
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.