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Ciaccio PJ , Shen HX , Kruh GD , Tew KD
Effects of chronic ethacrynic acid exposure on glutathione conjugation and MRP expression in human colon tumor cells
Biochemical and Biophysical Research Communications. 1996 May 6;222(1) :111-115
AbstractChronic exposure to ethacrynic acid of a subcloned HT29 human cion cancer cell line produces a 3- to 4-fold increase in the level of resistance to this agent. The resistant cells (HT6-8) have an enhanced capacity to metabolize the parent drug and efflux it from the cell. This is reflected in a 5-fold enhanced decompositioning rate constant for ethacrynic acid in HT6-8 (3.47 x 10(-3) min(-1)) versus wild type cells (1.58 x 10(-2) min(-1)). We observed that the glutathione conjugate of ethacrynic acid is an effective competitive inhibitor for binding to the multidrug resistance-associated protein by [S- 35]azidophenacyl-glutathione, a photoaffinity analog of glutathione. In addition, the HT6-8 cells overexpressed multidrug resistance-associated transcript 2- to 3-fold. These results suggest that resistance to ethacrynic acid results from a concerted, coordinate increase in defense mechanisms which detoxify the drug and remove its conjugate via plasma membrane efflux. (C) 1996 Academic Press, Inc.
NotesTimes Cited: 20 English Article UJ625 BIOCHEM BIOPHYS RES COMMUN