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

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 IC50 values of RRR-α-tocopherol for the purified isoenzymes of GST are much lower compared to the IC50 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. © 2003 Elsevier Science Ltd. All rights reserved.
Chemicals/CAS: alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; glutathione transferase, 50812-37-8; alpha-Tocopherol, 59-02-9; Antioxidants; Glutathione Transferase, EC 2.5.1.18; Isoenzymes