Inhibition of rat and human glutathione S-transferase isoenzymes by ethacrynic acid and its glutathione conjugate

Biochem Pharmacol. 1990 Oct 1;40(7):1631-5. doi: 10.1016/0006-2952(90)90465-w.


Ethacrynic acid, a potent inhibitor of glutathione S-transferases (GST), has been shown to enhance the cytotoxicity of chlorambucil in drug resistant cell lines, but a definite mechanism has not been established. Both covalent binding to GST and reversible inhibition of GST have been reported. In the present study no irreversible inhibition was observed: for all rat GST tested, inactivation was complete within 15 sec at 0 degree, and dialysis of GST after incubation with ethacrynic acid gave complete recovery of enzyme activity for all isoenzymes tested. Moreover, the inhibition was competitive towards 1-chloro-2,4-dinitrobenzene and non-competitive towards glutathione for rat isoenzyme 1-1. Strong inhibition of both human and rat GST of the alpha-, mu- and pi-classes was obtained with ethacrynic acid, while conjugation of ethacrynic acid with glutathione did not abolish its inhibiting properties. For the alpha-, mu- and pi-class I50 values (microM) were 4.6-6.0, 0.3-1.9 and 3.3-4.8, respectively for ethacrynic acid, and 0.8-2.8, less than 0.1-1.2 and 11.0, respectively for its glutathione conjugate. Of all isoenzymes tested the human isoenzyme mu is most sensitive to the action of both ethacrynic acid and its glutathione conjugate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dinitrochlorobenzene / pharmacology
  • Ethacrynic Acid / pharmacology*
  • Glutathione / pharmacology*
  • Glutathione Transferase / antagonists & inhibitors*
  • Humans
  • Isoenzymes / antagonists & inhibitors*
  • Kinetics
  • Male
  • Rats
  • Rats, Inbred Strains


  • Dinitrochlorobenzene
  • Isoenzymes
  • Glutathione Transferase
  • Glutathione
  • Ethacrynic Acid