<sc>L</sc>-Glutamate Enhances Methylmercury Toxicity by Synergistically Increasing Oxidative Stress

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  • Amonpatumrat Sirirat
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Japan Toxicology Graduate Program, Faculty of Science, Mahidol University, Thailand
  • Sakurai Hiroyuki
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Japan
  • Wiriyasermkul Pattama
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Japan Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Khunweeraphong Narakorn
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Japan Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Nagamori Shushi
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Tanaka Hidekazu
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Piyachaturawat Pawinee
    Toxicology Graduate Program, Faculty of Science, Mahidol University, Thailand Department of Physiology, Faculty of Science, Mahidol University, Thailand
  • Kanai Yoshikatsu
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan

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  • L-glutamate enhances methylmercury toxicity by synergistically increasing oxidative stress

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Abstract

Methylmercury (MeHg) is a well-known environmental toxicant. With its lipophilic nature and high reactivity to sulfhydryl 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 <sc>L</sc>-glutamate (<sc>L</sc>-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 <sc>L</sc>-Glu-elicited increase of MeHg toxicity. The effect was specific to <sc>L</sc>-Glu and <sc>L</sc>-α-aminoadipate, whereas <sc>D</sc>-Glu, <sc>L</sc>-aspartate, and <sc>D</sc>-aspartate were not effective. In addition, the cystine uptake by the cells was mostly mediated by a <sc>L</sc>-Glu/<sc>L</sc>-α-aminoadipate–sensitive amino acid transport system x−C. All these results suggest that the inhibition of system x−C by <sc>L</sc>-Glu underlies the enhancement of MeHg cytotoxicity. The enhancement was highly synergistic because MeHg and <sc>L</sc>-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.<br>

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