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Title: L-glutamate enhances methylmercury toxicity by synergistically increasing oxidative stress
Authors: Sirirat Amonpatumrat
Hiroyuki Sakurai
Pattama Wiriyasermkul
Narakorn Khunweeraphong
Shushi Nagamori
Hidekazu Tanaka
Pawinee Piyachaturawat
Yoshikatsu Kanai
Kyorin University School of Medicine
Osaka University
Mahidol University
Keywords: Biochemistry, Genetics and Molecular Biology;Pharmacology, Toxicology and Pharmaceutics
Issue Date: 28-Nov-2008
Citation: Journal of Pharmacological Sciences. Vol.108, No.3 (2008), 280-289
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 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-α-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-α-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. ©2008 The Japanese Pharmacological Society.
ISSN: 13478648
Appears in Collections:Scopus 2006-2010

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