Inhibition of human hepatic glutathione S-transferase isozymes by ethacrynic acid and its metabolites.
The comparative inhibition of ethacrynic acid (EA) and its known metabolites against glutathione S-transferase (GST) was investigated using human livers procured from kidney donors. EA and all three metabolites of EA had an inhibitory effect against conjugation between 1-chloro-2,4-dinitrobenzene (CDNB) and glutathione (GSH). The GSH adduct of EA (EA-GSH) was the most potent inhibitor of GSTs; EA-GSH was approximately one order of magnitude more potent than the parent EA, while L-cysteine conjugate of EA (EA-cysteine) and N-acetyl-L-cysteine conjugate of EA (EA-mercapturate) were approximately two orders of magnitude less potent than the parent EA. Further metabolism of EA-GSH conjugate is suggested to be a detoxification process in terms of GST activities.
Takamatsu
Y
Y
Department of Pharmacology, Faculty of Medicine, University of Toronto, Ontario, Canada.
Inaba
T
T
D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004137:Dinitrochlorobenzene / Q000378:metabolism; D004976:Ethacrynic Acid / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D004137:Dinitrochlorobenzene; D007527:Isoenzymes; D005982:Glutathione Transferase; D005978:Glutathione; D004976:Ethacrynic Acid