The human glutathione transferase P1-1 specific inhibitor TER 117 designedfor overcoming cytostatic-drug resistance is also a strong inhibitor of glyoxalase I

gamma-L-Glutamyl-S-(benzyl)-L-cysteinyl-R-(-)-phenylglycine (TER 117) has p reviously been developed for selective inhibition of human glutathione S-tr ansferase P1-1 (GST P1-1) based on the postulated contribution of this isoe nzyme to the development of drug resistance in cancer cells. In the present investigation, the inhibitory effect of TER 117 on the human glyoxalase sy stem was studied. Although designed as an inhibitor specific for GST P1-1, TER 117 also competitively inhibits glyoxalase I (K-I = 0.56 mu M). In cont rast, no inhibition of glyoxalase II was detected. Reduced glyoxalase activ ity is expected to raise intracellular levels of toxic 2-oxoaldehydes other wise 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 TE R 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 KI values at glutathione concentrations relevant to the intracellular milieu were in the micromolar range for both enzyme forms. Extrapolation to free e nzyme produced KI values of approximately 0.1 mu M for both isoenzymes, ref lecting 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 potenc y 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 o f chemotherapy.