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1.
Cell Biol Toxicol ; 23(6): 413-20, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17457679

ABSTRACT

Vanadium is an environmentally toxic metal with peculiar and sometimes contradictory cellular effects. It is insulin-mimetic, it can either stimulate cell growth or induce cell death, and it has both mutagenic and antineoplastic properties. However, the mechanisms involved in those effects are poorly understood. Several studies suggest that H(2)O(2) is involved in vanadate-induced cell death, but it is not known whether cellular sensitivity to vanadate is indeed related to H(2)O(2) generation. In the present study, the sensitivity of four cell lines from different origins (K562, K562-Lucena 1, MDCK, and Ma104) to vanadate and H(2)O(2) was evaluated and the production of H(2)O(2) by vanadate was analyzed by flow cytometry. We show that cell lines very resistant to H(2)O(2) (K562, K562-Lucena 1, and Ma104 cells) are much more sensitive to vanadate than MDCK, a cell line relatively susceptible to H(2)O(2), suggesting that vanadate-induced cytotoxicity is not directly related to H(2)O(2) responsiveness. In accordance, vanadate concentrations that reduced cellular viability to approximately 60-70% of the control (10 mumol/L) did not induce H(2)O(2) formation. A second hypothesis, that peroxovanadium (PV) compounds, produced once vanadate enters into the cells, are responsible for the cytotoxicity, was only partially confirmed because MDCK cells were resistant to both vanadate and PV compounds (10 micromol/L each). Therefore, our results suggest that vanadate toxicity occurs by two distinct pathways, one dependent on and one independent of H(2)O(2) production.


Subject(s)
Hydrogen Peroxide/metabolism , Vanadates/toxicity , Animals , Cell Death/drug effects , Dogs , Fluorescence , Haplorhini , Humans , Hydrogen Peroxide/pharmacology , K562 Cells , Oxidation-Reduction/drug effects , Rhodamines/metabolism
2.
Biochim Biophys Acta ; 1526(3): 293-300, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11410339

ABSTRACT

It is widely accepted that a prolonged ouabain blockade of the Na(+),K(+)-ATPase makes cells detach from each other and from the substrate, leading to their death and that cellular resistance to ouabain is due to the presence of isoforms of Na(+),K(+)-ATPase with low affinity to this glycoside. In the present work the effect of reduced glutathione in the response of two types of renal cells to ouabain: MDCK, a ouabain-sensitive cell line and Ma104, a ouabain-resistant one, was studied. Glutathione protected MDCK cells from ouabain toxicity and inhibition of glutathione synthesis by L-buthionine-S,R-sulfoximine sensitized Ma104 cells to ouabain. As glutathione is involved with multidrug resistance (MDR) in cells expressing the multidrug resistance-related protein MRP1 and as Ma104 cells have a MDR phenotype, it was investigated whether Ma104 cells express this protein. The expression of the MRP1-mRNA in Ma104 cells was detected by reverse transcriptase-polymerase chain reaction and ribonuclease protection assay, and the protein was detected by Western blotting and immunofluorescence. Treatment of Ma104 cells with ouabain increased MRP1-mRNA expression and altered the localization of MRP1 in these cells. Our results suggest that some cells may have mechanisms to protect themselves from ouabain toxicity and that MRP1 may have a role in controlling the toxic effects of ouabain.


Subject(s)
ATP-Binding Cassette Transporters/analysis , Antioxidants/pharmacology , Gene Expression Regulation/drug effects , Glutathione/pharmacology , Ouabain/toxicity , ATP-Binding Cassette Transporters/genetics , Animals , Blotting, Western , Buthionine Sulfoximine/pharmacology , Catalase/pharmacology , Cell Line/drug effects , Drug Resistance, Multiple/genetics , Fluorescent Antibody Technique , Glutathione/antagonists & inhibitors , Multidrug Resistance-Associated Proteins , Ouabain/antagonists & inhibitors , Phenotype , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Superoxide Dismutase/pharmacology
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