bcl-2 expression decreases methyl mercury-induced free-radical generation and cell killing in a neural cell line.
Methyl mercury neurotoxicity is associated with a broad range of neuropathologic and biochemical disturbances which include induction of oxidative injury. Treatment of the hypothalamic neural cell line GT1-7 with 10 microM methyl mercury (MeHg) for 3 h resulted in increased formation of reactive oxygen species (ROS), and decreased levels of reduced glutathione (GSH), associated with 20% cell death. Cells transfected with an expression construct for the anti-apoptotic proto-oncogene, bcl-2, displayed attenuated ROS induction and negligible cell death. Twenty-four-h exposure to 5 microM MeHg killed 56% of control cells, but only 19% of bcl-2-transfected cells. By using diethyl maleate to deplete cells of GSH, we demonstrate that the differential sensitivity to MeHg was not due solely to intrinsically different GSH levels. The data suggest that MeHg-mediated cell killing correlates more closely with ROS generation than with GSH levels and that bcl-2 protects MeHg-treated cells by suppressing ROS generation.
Sarafian
T A
TA
Department of Pathology, UCLA Center for Health Sciences 90024.
Vartavarian
L
L
Kane
D J
DJ
Bredesen
D E
DE
Verity
M A
MA
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D008767:Methylmercury Compounds / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D008767:Methylmercury Compounds; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D005978:Glutathione