Inhibition of glutathione S-transferase in rat hepatocytes by a glycine-tetrazole modified S-alkyl-GSH analogue.
Glutathione (GSH) conjugates inhibit enzymes that are involved in drug metabolism and drug resistance, but their cellular uptake is very low. To improve membrane-permeability, we synthesized a novel GSH-conjugate analogue with a tetrazole carboxylate isostere at the glycine position. Introduction of the tetrazole decreases inhibitory potency towards CDNB conjugation by glutathione S-transferase. However, the tetrazole derivative inhibited 2-bromoisovalerylurea conjugation in rat liver cytosol, as well as in hepatocytes.
Burg
Danny
D
Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, PO Box 9502, 2300RA, Leiden, The Netherlands. d.burg@lacdr.leidenuniv.nl
Hameetman
Liesbeth
L
Filippov
Dmitri V
DV
van der Marel
Gijs A
GA
Mulder
Gerard J
GJ
D000818:Animals; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D005998:Glycine / Q000737:chemistry*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D013379:Substrate Specificity; D013777:Tetrazoles / Q000737:chemistry*
D013777:Tetrazoles; C045574:1H-tetrazole; D005982:Glutathione Transferase; D005978:Glutathione; D005998:Glycine