Effects of chronic ethacrynic acid exposure on glutathione conjugation and MRP expression in human colon tumor cells.
Chronic exposure to ethacrynic acid of a subcloned HT29 human colon 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 [35S]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.
Ciaccio
P J
PJ
Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Shen
H
H
Kruh
G D
GD
Tew
K D
KD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001692:Biological Transport; D004334:Drug Administration Schedule; D018432:Drug Resistance, Multiple; D004976:Ethacrynic Acid / Q000008:administration & dosage* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005978:Glutathione; D004976:Ethacrynic Acid