TY - JOUR
T1 - Expression of multidrug resistance protein/GS-X pump and γ- glutamylcysteine synthetase genes is regulated by oxidative stress
AU - Yamane, Yoshiaki
AU - Furuichi, Masato
AU - Song, Renduo
AU - Van Nguyen, T.
AU - Mulcahy, R. Timothy
AU - Ishikawa, Toshihisa
AU - Kuo, M. Tien
PY - 1998/11/20
Y1 - 1998/11/20
N2 - Expression of the MRP1 gene encoding the GS-X pump and of the γ-GCSh gene encoding the heavy (catalytic) subunit of the γ-glutamylcysteine synthetase is frequently elevated in many drug-resistant cell lines and can be co-induced by many cytotoxic agents. However, mechanisms that regulate the expression of these genes remain to be elucidated. We report here that like γ-GCSh, the expression of MRP1 can be induced in cultured cells treated with pro-oxidants such as tert-butylhydroquinone, 2,3-dimethoxy-1,4- naphthoquinone, and menadione. Intracellular reactive oxygen intermediate (ROI) levels were increased in hepatoma cells treated with tert- butylhydroquinone for 2 h as measured by flow cytometry using an ROI-specific probe, dihydrorhodamine 123. Elevated GSH levels in stably γ-GCSh- transfected cell lines down-regulated endogenous MRP1 and γ-GCSh expression. ROI levels in these transfected cells were lower than those in the untransfected control. In the cell lines in which depleting cellular GSH pools did not affect the expression of the MRP1 and γ-GCSh genes, only minor increased intracellular levels of ROIs were observed. These results suggest that intracellular ROI levels play an important role in the regulation of MRP1 and γ-GCSh expression. Our data also suggest that elevated intracellular GSH levels not only facilitate substrate transport by the MRP1/GS-X pump as previously demonstrated, but also suppress MRP1 and γ- GCSh expression.
AB - Expression of the MRP1 gene encoding the GS-X pump and of the γ-GCSh gene encoding the heavy (catalytic) subunit of the γ-glutamylcysteine synthetase is frequently elevated in many drug-resistant cell lines and can be co-induced by many cytotoxic agents. However, mechanisms that regulate the expression of these genes remain to be elucidated. We report here that like γ-GCSh, the expression of MRP1 can be induced in cultured cells treated with pro-oxidants such as tert-butylhydroquinone, 2,3-dimethoxy-1,4- naphthoquinone, and menadione. Intracellular reactive oxygen intermediate (ROI) levels were increased in hepatoma cells treated with tert- butylhydroquinone for 2 h as measured by flow cytometry using an ROI-specific probe, dihydrorhodamine 123. Elevated GSH levels in stably γ-GCSh- transfected cell lines down-regulated endogenous MRP1 and γ-GCSh expression. ROI levels in these transfected cells were lower than those in the untransfected control. In the cell lines in which depleting cellular GSH pools did not affect the expression of the MRP1 and γ-GCSh genes, only minor increased intracellular levels of ROIs were observed. These results suggest that intracellular ROI levels play an important role in the regulation of MRP1 and γ-GCSh expression. Our data also suggest that elevated intracellular GSH levels not only facilitate substrate transport by the MRP1/GS-X pump as previously demonstrated, but also suppress MRP1 and γ- GCSh expression.
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U2 - 10.1074/jbc.273.47.31075
DO - 10.1074/jbc.273.47.31075
M3 - Article
C2 - 9813007
AN - SCOPUS:0032553308
SN - 0021-9258
VL - 273
SP - 31075
EP - 31085
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -