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. The synthesis and evaluation of a novel tetrazoyl-modified GSH-conjugate analogue is reported.