Thimerosal neurotoxicity is associated with glutathione depletion: protection with glutathione precursors.
Thimerosol is an antiseptic containing 49.5% ethyl mercury that has been used for years as a preservative in many infant vaccines and in flu vaccines. Environmental methyl mercury has been shown to be highly neurotoxic, especially to the developing brain. Because mercury has a high affinity for thiol (sulfhydryl (-SH)) groups, the thiol-containing antioxidant, glutathione (GSH), provides the major intracellular defense against mercury-induced neurotoxicity. Cultured neuroblastoma cells were found to have lower levels of GSH and increased sensitivity to thimerosol toxicity compared to glioblastoma cells that have higher basal levels of intracellular GSH. Thimerosal-induced cytotoxicity was associated with depletion of intracellular GSH in both cell lines. Pretreatment with 100 microM glutathione ethyl ester or N-acetylcysteine (NAC), but not methionine, resulted in a significant increase in intracellular GSH in both cell types. Further, pretreatment of the cells with glutathione ethyl ester or NAC prevented cytotoxicity with exposure to 15 microM Thimerosal. Although Thimerosal has been recently removed from most children's vaccines, it is still present in flu vaccines given to pregnant women, the elderly, and to children in developing countries. The potential protective effect of GSH or NAC against mercury toxicity warrants further research as possible adjunct therapy to individuals still receiving Thimerosal-containing vaccinations.
James
S J
SJ
Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. jamesjill@uams.edu
Slikker
William
W
Melnyk
Stepan
S
New
Elizabeth
E
Pogribna
Marta
M
Jernigan
Stefanie
S
D000111:Acetylcysteine / Q000494:pharmacology; D000891:Anti-Infective Agents, Local / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D003553:Cystine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004563:Electrochemistry; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D009474:Neurons / Q000187:drug effects; D013849:Thimerosal / Q000037:antagonists & inhibitors / Q000633:toxicity*
D000891:Anti-Infective Agents, Local; D003470:Culture Media; D013849:Thimerosal; D003553:Cystine; C042431:S-ethyl glutathione; D005978:Glutathione; D000111:Acetylcysteine