Homologous metabolic and gene activating routes for vitamins E and K
Introduction
Vitamin E describes a family of lipophilic micronutrients consisting of four tocopherols and four tocotrienols that consist of a chromanol ring and a side chain. Tocopherols and tocotrienols are designated α,β,γ and δ according to the number and position of methyl groups on the chromanol ring. Tocopherols and tocotrienols differ in their side chain, which is saturated in tocopherols or has three double bonds in tocotrienols. α-Tocopherol is by far the most abundant and biologically the most active member of the vitamin E family (for review see Brigelius-Flohé et al., 2002; Brigelius-Flohé and Traber, 1999; Traber and Sies, 1996).
Section snippets
Functions of vitamin E
All forms of vitamin E have antioxidant properties in vitro. This by itself, however, cannot explain the vital functions of α-tocopherol in the reproduction of rats discovered by Evans and Bishop already 80 years ago (Evans and Bishop, 1922). More recently other functions of individual forms of vitamin E have been described such as the α-tocopherol-specific inhibition of the proliferation of smooth muscle cells, platelet adhesion (Szuwart et al., 2000), expression of VCAM-l (Zapolska-Downar et
Metabolism of vitamin E
Tocopherols and tocotrienols are degraded by truncation of the side chain via β-oxidation resulting in the final metabolites CEHCs (carboxyethyl hydroxychromans) and their precursors CMBHCs (carboxymethylbutyl hydroxychromans). This has been proven by the identification of all possible intermediates arising from tocopherol and tocotrienol metabolism (Birringer et al., 2002) (Fig. 1). For β-oxidation an initial ω-hydroxylation is required as known for long chain fatty acids. This ω-hydroxylation
Vitamin E and drug metabolism
Many cytochrome P450 enzymes are induced by their substrates themselves. This is achieved via the activation of nuclear receptors, such as peroxisome proliferator activated receptors (PPAR), liver X receptor (LXR), vitamin D receptor (VDR), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), or the pregnane X receptor (PXR) (Drocourt et al., 2002; Waxman, 1999). As recently demonstrated also vitamin E induces endogenous CYP3A4 and CYP3A5 in HepG2 cells (Landes et al., 2003).
Metabolism of vitamin K
Vitamin K was discovered in the early 1930s (Dam and Schoenheyder, 1935). Since it was believed to play an exclusive role in the process of blood coagulation. Only recently it became clear that it is involved in the formation of Gla-containing proteins. These include osteocalcin, which regulates bone growth (Ducy et al., 1996), or matrix gla-proteins, which prevent vascular mineralization (Luo et al., 1997), functions as essential as that of vitamin E. Also vitamin K covers several vitamers,
Metabolism of coenzyme Q
Coenzyme Q (ubiquinone) is an essential component of the respiratory chain. Electrons are shuttled from complex I and complex II to coenzyme Q, which transfers them to cytochrome reductase. Coenzyme Q is the only electron carrier in the mitochondrial electron transport system, which is not permanently bound or attached to a protein. It is a quinone derivative with a long side chain composed of a varying number of isoprene units. In mammals, the most common form contains ten units (Q10). The
Homologous routes
Comparison of metabolites of vitamins E, K and Q10 reveals striking similarities. K acid 1 and Q acid 1 obviously are the second final metabolites as are the CMBHCs derived from individual forms of vitamin E, whereas K acid 2 and Q acid 2 correspond to CEHCs, the final products of vitamin E metabolism. This suggests that vitamins E, K and Q10 are metabolized via the same mechanism. The similarities led us to ask whether also vitamins K and Q10 were able to induce a PXR regulated reporter gene.
Conclusion
Taken together, fat-soluble vitamins and compounds with an isoprenoid side chain obviously are metabolized by side chain degradation via an initial ω-hydroxylation and subsequent β-oxidation. ω-Hydroxylation of vitamin E is catalyzed by cytochrome P450 enzymes and this is most likely so for vitamins K and Q10, although this needs to be demonstrated. Thus the CYPs responsible for the elimination of xenobiotics also remove lipophilic vitamins if administered beyond physiological needs. The
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft, DFG, Br 778/6-1.
References (36)
- et al.
Modulation of alpha-tropomyosin expression by alpha-tocopherol in rat vascular smooth muscle cells
FEBS Lett.
(1999) - et al.
Tocopherols are metabolized in HepG2 cells by side chain omega-oxidation and consecutive beta-oxidation
Free Rad. Biol. Med.
(2001) - et al.
Identities and differences in the metabolism of tocotrienols and tocopherols in HepG2 cells
J. Nutr.
(2002) - et al.
Alpha-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity
Arch. Biochem. Biophys.
(1991) - et al.
The European perspective on vitamin E: current knowledge and future research
Am. J. Clin. Nutr.
(2002) - et al.
Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells
Free Rad. Biol. Med.
(1997) - et al.
Expression of CYP3A4, CYP2B6, and CYP2C9 is regulated by the vitamin D receptor pathway in primary human hepatocytes
J. Biol. Chem.
(2002) - et al.
Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs
FEBS Lett.
(1997) - et al.
Vitamin E activates gene expression via the pregnane X receptor
Biochem. Pharmacol.
(2003) - et al.
Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase
J. Biol. Chem.
(1993)