The human glutathione transferase P1-1 specific inhibitor TER 117 designed for overcoming cytostatic-drug resistance is also a strong inhibitor of glyoxalase I.
gamma-L-Glutamyl-S-(benzyl)-L-cysteinyl-R-(-)-phenylglycine (TER 117) has previously been developed for selective inhibition of human glutathione S-transferase P1-1 (GST P1-1) based on the postulated contribution of this isoenzyme to the development of drug resistance in cancer cells. In the present investigation, the inhibitory effect of TER 117 on the human glyoxalase system was studied. Although designed as an inhibitor specific for GST P1-1, TER 117 also competitively inhibits glyoxalase I (K(I) = 0.56 microM). In contrast, no inhibition of glyoxalase II was detected. Reduced glyoxalase activity is expected to raise intracellular levels of toxic 2-oxoaldehydes otherwise eliminated by glyoxalase I. The resulting toxicity would accompany the potentiation of cytostatic drugs, caused by inhibition of the detoxication effected by GST P1-1. TER 117 was designed for efficient inhibition of the most abundant form GST P1-1/Ile105. Therefore, the inhibitory effect of TER 117 on a second allelic variant GST P1-1/Val105 was also studied. TER 117 was shown to competitively inhibit both GST P1-1 variants. The apparent K(I) values at glutathione concentrations relevant to the intracellular milieu were in the micromolar range for both enzyme forms. Extrapolation to free enzyme produced K(I) values of approximately 0.1 microM for both isoenzymes, reflecting the high affinity of GST P1-1 for the inhibitor. Thus, the allelic variation in position 105 of GST P1-1 does not affect the inhibitory potency of TER 117. The inhibitory effects of TER 117 on GST P1-1 and glyoxalase I activities may act in synergy in the cell and improve the effectiveness of chemotherapy.
Johansson
A S
AS
Department of Biochemistry, Uppsala University, Biomedical Center, Uppsala, Sweden.
Ridderström
M
M
Mannervik
B
B
D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009842:Oligopeptides; C085408:gamma-glutaminyl-S-(4-chlorobenzyl)cysteinyl-phenylglycine; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007791:Lactoylglutathione Lyase