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DIFFERENTIAL EFFECTS OF PYRETHROIDS ON VOLUME‐SENSITIVE ANION AND ORGANIC OSMOLYTE PATHWAYS
Author(s) -
Culliford Steve J,
Borg John J,
O'Brien Martin J,
Kozlowski Roland Z
Publication year - 2004
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2004.03965.x
Subject(s) - hela , efflux , taurine , chemistry , pharmacology , glioma , myocyte , cell culture , patch clamp , biochemistry , microbiology and biotechnology , biophysics , cell , biology , cancer research , receptor , amino acid , genetics
SUMMARY 1. There are no effective ways of screening for potential modulators of volume‐regulated anion channels in their native cell type. Generally, cell lines are used for this purpose. Using HeLa and C6 glioma cells, we identified the pyrethroids as a novel class of compounds that inhibit taurine efflux through volume‐regulated anion transport pathways in these cells. Subsequently, we examined their effects on volume‐regulated anion channels in guinea‐pig ventricular myocytes to determine whether results obtained using cell lines could be extrapolated to other tissues. 2. Tetramethrin inhibited taurine efflux in both HeLa and C6 glioma cells with K i values of approximately 26 and 16 µmol/L, respectively. Bioallethrin and fenpropathrin inhibited volume‐sensitive taurine efflux from C6 glioma cells, but not from HeLa cells. The K i values for bioallethrin and fenpropathrin were 70 and 59 µmol/L, respectively. 3. Volume‐sensitive I – efflux was observed in HeLa cells but not in C6 glioma cells, suggesting that the taurine efflux pathway in C6 glioma cells may be different to that of the I – efflux pathway. Cyfluthrin, tetramethrin, fenpropathrin, tefluthrin and bioallethrin all significantly inhibited volume‐sensitive I – efflux from HeLa cells at 100 µmol/L. 4. Patch‐clamp experiments have shown inhibition of I Cl,vol in guinea‐pig ventricular myocytes by fenpropathrin, but not tetramethrin or cypermethrin, at 100 µmol/L. This revealed that further differences exist between I Cl,vol in guinea‐pig ventricular myocytes and the anion transport pathways in C6 glioma and HeLa cells. 5. In conclusion, we have shown that pyrethroids differentially inhibit volume‐regulated anion and taurine efflux in a number of cell types. Because these compounds have different effects in different cells, it is likely that: (i) more than one pathway is involved in the volume‐sensitive transport of anions and organic osmolytes; and (ii) the molecular identities of the channels underlying anion transport are different. Finally, for the reasons given above, care should be taken when extrapolating data from one cell type to another. However, in the absence of an existing high‐throughput screen, taurine efflux still represents a viable route for the identification of potential modulators of volume‐regulated ion channels.