Landes Nico, Pfluger Paul, Kluth Dirk, Birringer Marc, Rühl Ralph, Böl Gaby-Fleur, Glatt Hansruedi, Brigelius-Flohé Regina
Department of Vitamins and Atherosclerosis, German Institute of Human Nutrition, D-14558 Bergholz-Rehbrücke, Germany.
Biochem Pharmacol. 2003 Jan 15;65(2):269-73. doi: 10.1016/s0006-2952(02)01520-4.
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.
生育酚和生育三烯酚通过侧链降解进行代谢，首先是ω-氧化，随后是β-氧化。ω-氧化由细胞色素P450（CYP）酶进行，这些酶通常受其底物自身的调节。此处呈现的结果表明，所有形式的维生素E都能够通过孕烷X受体（PXR）激活基因表达，PXR是一种调节多种药物代谢酶的核受体。在转染了人PXR和与两个PXR反应元件相连的氯霉素乙酰转移酶（CAT）基因的HepG2细胞中，α-和γ-生育三烯酚对CAT活性的诱导作用最强，其次是利福平、δ-、α-和γ-生育酚。诱导效力呈浓度依赖性；当省略与PXR的共转染时反应较低，这突出了其特异性。γ-生育三烯酚是PXR最有效的激活剂，它使内源性CYP3A4和CYP3A5 mRNA上调，其效力与利福平相同。这表明维生素E的各个形式可能会干扰药物的代谢和疗效。
