title: Tocotrienols inhibit human glutathione S-transferase P1-1.
abstract: Tocopherols and tocotrienols are food ingredients that are believed to have a positive effect on health. The most studied property of both groups of compounds is their antioxidant action. Previously, we found that tocopherols and diverse tocopherol derivatives can inhibit the activity of human glutathione S-transferase P1-1 (GST P1-1). In this study we found that GST P1-1 is also inhibited, in a concentration-dependent manner, by alpha- and gamma-tocotrienol. The concentration giving 50% inhibition of GST P1-1 is 1.8 +/- 0.1 microM for alpha-tocotrienol and 0.7 +/- 0.1 microM for gamma-tocotrienol. This inhibition of GST P1-1 is noncompetitive with respect to both substrates CDNB and GSH. We also examined the 3D structure of GST P1-1 for a possible tocopherol/tocotrienol binding site. The enzyme contains a very hydrophobic pit-like structure where the phytyl tail of tocopherols and tocotrienols could fit in. Binding of tocopherol and tocotrienol to this hydrophobic region might lead to bending of the 3D structure. In this way tocopherols and tocotrienols can inhibit the activity of the enzyme; this inhibition can have far-reaching implications for humans.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Universiteit Maastricht, The Netherlands. R.vanHaaften@farmaco.unimaas.nl
authors.forename: Rachel I M
authors.initials: RI
authors.lastname: van Haaften
authors.forename: Guido R M M
authors.initials: GR
authors.lastname: Haenen
authors.forename: Chris T A
authors.initials: CT
authors.lastname: Evelo
authors.forename: Aalt
authors.initials: A
authors.lastname: Bast
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001665:Binding Sites; D004137:Dinitrochlorobenzene / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D024508:Tocotrienols / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004137:Dinitrochlorobenzene; D007527:Isoenzymes; D024508:Tocotrienols; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D005978:Glutathione