Induction of drug metabolizing enzymes by vitamin E.
Vitamin E is an essential micronutrient involved in various processes relevant to human health and disease. Although it has long been considered just as an antioxidant, it has now become clear that vitamin E has functions far exceeding that as an antioxidant. These include regulation of cellular signaling processes and gene expression. Expression control of enzymes involved in drug metabolism was recognized during the investigation of vitamin E degradation. Vitamin E is metabolized by side chain degradation initiated by an omega-hydroxylation, catalyzed by a cytochrome P450 enzyme (CYP). This mechanism is identical for all forms of vitamin E. The degree to which they are degraded, however, varies dramatically, and may, in part, explain their different biological activities. CYPs degrade various endogenous and exogenous compounds and many of them are induced by their substrates. Also, gamma-tocotrienol, identified as substrate of CYPs, increased endogenous CYP3A4 in human HepG2 cells. In two studies with mice undertaken independently, alpha-tocopherol induced Cyp3a11, the murine homolog to human CYP3A4, whereas neither gamma-tocopherol nor gamma-tocotrienol, due to rapid degradation, showed any effect. CYPs are induced via the activation of the pregnane-X-receptor (PXR), a member of the family of nuclear receptors. They are activated by a large number of lipophilic xenobiotics. Also, vitamin E induced a reporter gene driven by PXR. The induction was highest with alpha- and gamma-tocotrienol and low but significant with alpha-tocopherol. This roughly correlates with the in vitro binding of vitamin E to PXR. These findings reveal that, in principle, vitamin E is able to directly influence gene activity. They also raise the question of whether vitamin E may interfere with drug metabolism in humans. Related research is urgently deeded.
Brigelius-Flohé
Regina
R
Department of Biochemistry of Micronutrients, German Institute of Human Nutrition, Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany. flohe@mail.dife.de
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D004364:Pharmaceutical Preparations / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology* / Q000502:physiology
D000975:Antioxidants; D004364:Pharmaceutical Preparations; D014810:Vitamin E; D003577:Cytochrome P-450 Enzyme System