Homologous metabolic and gene activating routes for vitamins E and K

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Abstract

Vitamins E and K share structurally related side chains and are degraded to similar final products. For vitamin E the mechanism has been elucidated as initial ω-hydroxylation and subsequent β-oxidation. For vitamin K the same mechanism can be suggested analogously. ω-Hydroxylation of vitamin E is catalyzed by cytochrome P450 enzymes, which often are induced by their substrates themselves via the activation of the nuclear receptor PXR. Vitamin E is able to induce CYP3A-forms and to activate a PXR-driven reporter gene. It is shown here that K-type vitamins are also able to activate PXR. A ranking showed that compounds with an unsaturated side chain were most effective, as are tocotrienols and menaquinone-4 (vitamin K2), which activated the reporter gene 8–10-fold. Vitamers with a saturated side chain, like tocopherols and phylloquinone were less active (2–5-fold activation). From the fact that CYPs commonly responsible for the elimination of xenobiotics are involved in the metabolism of fat-soluble vitamins and the ability of the vitamins to activate PXR it can be concluded that supranutritional amounts of these vitamins might be considered as foreign.

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.

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