Vitamin E activates gene expression via the pregnane X receptor.
Tocopherols and tocotrienols are metabolized by side chain degradation via initial omega-oxidation and subsequent beta-oxidation. omega-Oxidation is performed by cytochrome P450 (CYP) enzymes which are often regulated by their substrates themselves. Results presented here show that all forms of Vitamin E are able to activate gene expression via the pregnane X receptor (PXR), a nuclear receptor regulating a variety of drug metabolizing enzymes. In HepG2 cells transfected with the human PXR and the chloramphenicol acetyl transferase (CAT) gene linked to two PXR responsive elements, CAT activity was most strongly induced by alpha- and gamma-tocotrienol followed by rifampicin, delta-, alpha- and gamma-tocopherol. The inductive efficacy was concentration-dependent; its specificity was underscored by a lower response when cotransfection with PXR was omitted. Up-regulation of endogenous CYP3A4 and CYP3A5 mRNA was obtained by gamma-tocotrienol, the most potent activator of PXR, with the same efficacy as with rifampicin. This points to a potential interference of individual forms of Vitamin E with the metabolism and efficacy of drugs.
Landes
Nico
N
Department of Vitamins and Atherosclerosis, German Institute of Human Nutrition, D-14558 Bergholz-Rehbrücke, Germany.
Pfluger
Paul
P
Kluth
Dirk
D
Birringer
Marc
M
Rühl
Ralph
R
Böl
Gaby-Fleur
GF
Glatt
Hansruedi
H
Brigelius-Flohé
Regina
R
D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000502:physiology*; D011987:Receptors, Steroid / Q000187:drug effects / Q000502:physiology*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D014810:Vitamin E / Q000494:pharmacology*
D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System