Effects of chronic ethacrynic acid exposure on glutathione conjugation and MRP expression in human colon tumor cells

Biochem Biophys Res Commun. 1996 May 6;222(1):111-5. doi: 10.1006/bbrc.1996.0706.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Biological Transport
  • Drug Administration Schedule
  • Drug Resistance, Multiple*
  • Ethacrynic Acid / administration & dosage*
  • Ethacrynic Acid / metabolism
  • Glutathione / metabolism*
  • Humans
  • Tumor Cells, Cultured


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Glutathione
  • Ethacrynic Acid