Inhibition of various glutathione S-transferase isoenzymes by RRR-alpha-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-alpha-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-alpha-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-alpha-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-alpha-tocopherol. The IC(50) values of RRR-alpha-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-alpha-tocopherol to proteins, e.g. albumin and hemoglobin, with higher affinity than to GST; so more RRR-alpha-tocopherol is needed to inhibit the enzyme. However, the inhibition of GSTs by RRR-alpha-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-alpha-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.
van Haaften
Rachel I M
RI
Department of Pharmacology and Toxicology, Faculty of Medicine, Universiteit Maastricht, 6200 MD, Maastricht, The Netherlands. rachel.vanhaaften@bigcat.unimaas.nl
Haenen
Guido R M M
GR
van Bladeren
Peter J
PJ
Bogaards
Jan J P
JJ
Evelo
Chris T A
CT
Bast
Aalt
A
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology*; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes; D008099:Liver / Q000201:enzymology; D024502:alpha-Tocopherol / Q000494:pharmacology*
D000975:Antioxidants; D007527:Isoenzymes; D005982:Glutathione Transferase; D024502:alpha-Tocopherol