Abstract
γ-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 μM). 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 apparentK I values at glutathione concentrations relevant to the intracellular milieu were in the micromolar range for both enzyme forms. Extrapolation to free enzyme producedK I values of approximately 0.1 μM 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.
Footnotes
- Received July 13, 1999.
- Accepted November 12, 1999.
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Send reprint requests to: Dr. Bengt Mannervik, Department of Biochemistry, Uppsala University, Biomedical Center, Box 576, SE-751 23 Uppsala, Sweden. E-mail:Bengt.Mannervik{at}biokem.uu.se
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This work was supported by the Swedish Cancer Society. A.-S.J. is a recipient of a stipend from the Lilly and Sven Lawski Fund.
- The American Society for Pharmacology and Experimental Therapeutics
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