Overexpression of GlutathioneS-Transferase II and Multidrug Resistance Transport Proteins Is Associated with Acquired Tolerance to Inorganic Arsenic
- 1 August 2001
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 60 (2), 302-309
- https://doi.org/10.1124/mol.60.2.302
Abstract
Recent work shows that long-term exposure to low levels of arsenite induces malignant transformation in a rat liver epithelial cell line. Importantly, these chronic arsenic-exposed (CAsE) cells also develop self-tolerance to acute arsenic exposure. Tolerance is accompanied by reduced cellular arsenic accumulation, suggesting a mechanistic basis for reduced arsenic sensitivity. The present study examined the role of xenobiotic export pumps in acquired arsenic tolerance. Microarray analysis of CAsE cells showed increased expression of the genes encoding for glutathione S-transferase Π (GST-Π), multidrug resistance-associated protein genes (MRP1/MRP2, which encode for the efflux transporter Mrp1/Mrp2) and the multidrug resistance gene (MDR1, which encodes for the efflux transporter P-glycoprotein). These findings were confirmed at the transcription level by reverse transcription-polymerase chain reaction and at the translation level by Western-blot analysis. Acquired arsenic tolerance was abolished when cells were exposed to ethacrynic acid (an inhibitor of GST-Π), buthionine sulfoximine (a glutathione synthesis inhibitor), MK571 (a specific inhibitor for Mrps), and PSC833 (a specific inhibitor for P-glycoprotein) in dose-dependent fashions. MK571, PSC833, and buthionine sulfoximine markedly increased cellular arsenic accumulation. Consistent with a role for multidrug resistance efflux pumps in arsenic resistance, CAsE cells were found to be cross-resistant to cytotoxicity of several anticancer drugs, such as vinblastine, doxorubicin, actinomycin-D, and cisplatin, that are also substrates for Mrps and P-glycoprotein. Thus, acquired tolerance to arsenic is associated with increased expression GST-Π, Mrp1/Mrp2 and P-glycoprotein, which function together to reduce cellular arsenic accumulation.Keywords
This publication has 29 references indexed in Scilit:
- The MRP2/cMOAT Transporter and Arsenic-Glutathione Complex Formation Are Required for Biliary Excretion of ArsenicJournal of Biological Chemistry, 2000
- Metallothionein-I/II Null Mice Are More Sensitive than Wild-Type Mice to the Hepatotoxic and Nephrotoxic Effects of Chronic Oral or Injected Inorganic ArsenicalsToxicological Sciences, 2000
- BIOCHEMICAL, CELLULAR, AND PHARMACOLOGICAL ASPECTS OF THE MULTIDRUG TRANSPORTERAnnual Review of Pharmacology and Toxicology, 1999
- Complete Remission after Treatment of Acute Promyelocytic Leukemia with Arsenic TrioxideNew England Journal of Medicine, 1998
- Effect of Glutathione Depletion and Metallothionein Gene Expression on Arsenic-Induced Cytotoxicity and c-myc Expression in VitroToxicological Sciences, 1998
- Promotion of Rat Hepatocarcinogenesis by Dimethylarsinic Acid: Association with Elevated Ornithine Decarboxylase Activity and Formation of 8‐Hydroxydeoxyguanosine in the LiverJapanese Journal of Cancer Research, 1997
- Efflux-Mediated Resistance to Arsenicals in Arsenic-Resistant and -Hypersensitive Chinese Hamster CellsToxicology and Applied Pharmacology, 1996
- Cross-resistance between cisplatin, antimony potassium tartrate, and arsenite in human tumor cells.JCI Insight, 1995
- The Leukotriene LTD4 Receptor Antagonist Mk571 Specifically Modulates MRP Associated Multidrug ResistanceBiochemical and Biophysical Research Communications, 1995
- Quercetin, a bioflavonoid, inhibits the increase of human multidrug resistance gene (MDR1) expression caused by arseniteFEBS Letters, 1992