Inhibition of various glutathione S-transferase isoenzymes by RRR-α-tocopherol

Abstract

The activity of human cytosolic glutathione S-transferases (GSTs) can positively or negatively be changed by various compounds. It is for instance known that RRR-α-tocopherol inhibits GST P1-1 [Haaften van R.I.M. et al. (2001) Alpha-tocopherol inhibits human glutathione S-transferase pi. BBRC 280, 631–633]. The effect of RRR-α-tocopherol on the other isoenzymes of GST in purified forms of the isoenzymes and in human liver cytosol (GST M and GST A) and lysate of human erythrocytes (GST P) is studied. It is found that all isoenzymes (purified enzymes and enzymes present in homogenates) are inhibited, in a concentration-dependent way, by RRR-α-tocopherol. GST P is in both cases inhibited with the highest potency compared to the other isoenzymes. It also appeared that the purified GST P1-1 isoenzyme is non-competitively inhibited by RRR-α-tocopherol. The IC 50 values of RRR-α-tocopherol for the purified isoenzymes of GST are much lower compared to the IC 50 values for human lysate and human liver cytosol. This is probably due to binding of RRR-α-tocopherol to proteins, e.g. albumin and hemoglobin, with higher affinity than to GST; so more RRR–α-tocopherol is needed to inhibit the enzyme. However, the inhibition of GSTs by RRR–α-tocopherol can still be of physiological relevance, because due to dermal application of cosmetic products very high concentrations vitamin E can be reached in the skin, where GST P1-1 is present. RRR-α-tocopherol might also be a good lead compound for the development of a new class of inhibitors of GST that can be used as adjuvant in cancer therapy.