L-glutamate enhances methylmercury toxicity by synergistically increasing oxidative stress.
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.
Amonpatumrat
Sirirat
S
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Tokyo, Japan.
Sakurai
Hiroyuki
H
Wiriyasermkul
Pattama
P
Khunweeraphong
Narakorn
N
Nagamori
Shushi
S
Tanaka
Hidekazu
H
Piyachaturawat
Pawinee
P
Kanai
Yoshikatsu
Y
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
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