Elevated reactive oxygen species but not glutathione regulate mercury resistance to AML-2/DX100 cells.
The multidrug resistance-associated protein (MRP1) mediates cellular efflux of various xenobiotics and cellular resistance to heavy metals. Previously we reported that MRP1 mediates resistance to mercury exposure and possible mechanism mediating MRP1 expression after mercury exposure. This study was designed to investigate the role of reactive oxygen species (ROS) and glutathione on the resistance of AML-2/DX100 cells to mercuric chloride. The MRP1 overexpressing cells (AML-2/DX100) cells showed less scavenging activity to ROS induced by mercury while no difference in the basal glutathione levels between AML-2/WT and AML-2/DX100 cells. Mercury induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) but not c-jun-N-terminal kinase in AML-2/DX100 cells. The specific inhibitor for p38 MAPK and ERK, and antioxidant decreased the production of MRP1 and therefore resistance of AML-2/DX100 cells against mercury exposure. These results suggest that induction of ROS and downstream p38 MAPK and ERK were involved in the resistance of cells to mercury by expression MRP1 in AML-2/DX100 cells.
Choi
Cheol-Hee
CH
Department of Pharmacology, College of Medicine, Chosun University, Gwangju, Republic of Korea.
Bark
Hyun
H
Chung
Jae Myung
JM
Park
Eui Kyun
EK
Kim
Sang-Hyun
SH
D000111:Acetylcysteine / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008627:Mercuric Chloride / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000111:Acetylcysteine; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D005978:Glutathione; D006861:Hydrogen Peroxide; D007093:Imidazoles; D008627:Mercuric Chloride; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; D011725:Pyridines; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D048051:p38 Mitogen-Activated Protein Kinases; C020972:pyrrolidine dithiocarbamic acid; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C421109:multidrug resistance-associated protein 1