title: L-glutamate enhances methylmercury toxicity by synergistically increasing oxidative stress.
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-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.
authors.affiliation: Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Sirirat
authors.initials: S
authors.lastname: Amonpatumrat
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Pattama
authors.initials: P
authors.lastname: Wiriyasermkul
authors.forename: Narakorn
authors.initials: N
authors.lastname: Khunweeraphong
authors.forename: Shushi
authors.initials: S
authors.lastname: Nagamori
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Pawinee
authors.initials: P
authors.lastname: Piyachaturawat
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D015074:2-Aminoadipic Acid / Q000378:metabolism; D000111:Acetylcysteine / Q000494:pharmacology; D027182:Amino Acid Transport System y+ / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008767:Methylmercury Compounds / Q000633:toxicity*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D027182:Amino Acid Transport System y+; D000975:Antioxidants; D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D017382:Reactive Oxygen Species; D015074:2-Aminoadipic Acid; D018698:Glutamic Acid; D005978:Glutathione; D000111:Acetylcysteine