Mercury induces multidrug resistance-associated protein gene through p38 mitogen-activated protein kinase.
The multidrug resistance-associated protein (MRP1) belongs to a drug efflux membrane pump that confers multidrug resistance to the cells. The MRP1 mediates the cellular efflux of various xenobiotics including heavy metals and mediates cellular resistance to heavy metals. Mercury is a well-known health hazard and an environmental contaminant. Recently, information about the uptake of the heavy metals such as mercury has been suggested. However, little is known regarding molecular mechanisms of exporting mercury. This study was designed to determine if mercury could be extruded by MRP1 in acute myeloid leukemia cells (AML-2). The MRP-1-overexpressing AML-2/DX100 cells showed a higher resistance to mercury than AML-2/WT. Probenecid, which is a specific MRP1 inhibitor, decreased the resistance to mercury. Exposing the AML-2 cells to mercury-induced MRP1 gene expression and production without altering the MRP1 activity. Mercury activated p38 mitogen-activated protein kinase (MAPK) and SB 203580, a specific p38 MAPK inhibitor, blocked the mercury-induced MRP1 production. These results suggest that MRP1 can control mercury and p38 MAPK mediates the mercury-induced MRP1 gene expression.
Kim
Sang Hyun
SH
Research Center for Resistant Cells, Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501-759, South Korea.
Bark
Hyun
H
Choi
Cheol Hee
CH
D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019742:Chemokines, CC / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008628:Mercury / Q000633:toxicity*; D011725:Pyridines / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013778:Tetrazolium Salts; D013844:Thiazoles; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D013778:Tetrazolium Salts; D013844:Thiazoles; C070959:Ccl6 protein, mouse; D012313:RNA; D048051:p38 Mitogen-Activated Protein Kinases; C022616:thiazolyl blue; D008628:Mercury; C093642:SB 203580