Expression of multidrug resistance protein/GS-X pump and γ- glutamylcysteine synthetase genes is regulated by oxidative stress

Yoshiaki Yamane, Masato Furuichi, Renduo Song, T. Van Nguyen, R. Timothy Mulcahy, Toshihisa Ishikawa, M. Tien Kuo

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)31075-31085
Number of pages11
JournalJournal of Biological Chemistry
Volume273
Issue number47
DOIs
Publication statusPublished - Nov 20 1998

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Glutamate-Cysteine Ligase
P-Glycoproteins
Oxidative stress
Oxidative Stress
Genes
Cells
Oxygen
Gene encoding
Cell Line
Gene Expression
Vitamin K 3
Flow cytometry
Cytotoxins
Hepatocellular Carcinoma
Cultured Cells
Reactive Oxygen Species
Catalytic Domain
Flow Cytometry
glutathione transporter
Substrates

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Expression of multidrug resistance protein/GS-X pump and γ- glutamylcysteine synthetase genes is regulated by oxidative stress. / Yamane, Yoshiaki; Furuichi, Masato; Song, Renduo; Van Nguyen, T.; Mulcahy, R. Timothy; Ishikawa, Toshihisa; Kuo, M. Tien.

In: Journal of Biological Chemistry, Vol. 273, No. 47, 20.11.1998, p. 31075-31085.

Research output: Contribution to journalArticle

Yamane, Yoshiaki ; Furuichi, Masato ; Song, Renduo ; Van Nguyen, T. ; Mulcahy, R. Timothy ; Ishikawa, Toshihisa ; Kuo, M. Tien. / Expression of multidrug resistance protein/GS-X pump and γ- glutamylcysteine synthetase genes is regulated by oxidative stress. In: Journal of Biological Chemistry. 1998 ; Vol. 273, No. 47. pp. 31075-31085.
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