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 omega-hydroxylation and subsequent beta-oxidation. For vitamin K the same mechanism can be suggested analogously. omega-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 K(2)), 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.
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The oil palm (Elaeis guineensis) is native to many West African countries, where local populations have used its oil for culinary and other purposes. Large-scale plantations, established principally in tropical regions (Asia, Africa and Latin America), are mostly aimed at the production of oil, which is extracted from the fleshy mesocarp of the palm fruit, and endosperm or kernel oil. Palm oil is different from other plant and animal oils in that it contains 50% saturated fatty acids, 40% unsaturated fatty acids, and 10% polyunsaturated fatty acids. The fruit also contains components that can endow the oil with nutritional and health beneficial properties. These phytonutrients include carotenoids (alpha-,beta-,and gamma-carotenes), vitamin E (tocopherols and tocotrienols), sterols (sitosterol, stigmasterol and campesterol), phospholipids, glycolipids and squalene. In addition, it is recently reported that certain water-soluble powerful antioxidants, phenolic acids and flavonoids, can be recovered from palm oil mill effluent. Owing to its high content of phytonutrients with antioxidant properties, the possibility exists that palm fruit offers some health advantages by reducing lipid oxidation, oxidative stress and free radical damage. Accordingly, use of palm fruit or its phytonutrient-rich fractions, particularly water-soluble antioxidants, may confer some protection against a number of disorders or diseases including cardiovascular disease, cancers, cataracts and macular degeneration, cognitive impairment and Alzheimer’s disease. However, whilst prevention of disease through use of these phytonutrients as in either food ingredients or nutraceuticals may be a worthwhile objective, dose response data are required to evaluate their pharmacologic and toxicologic effects. In addition, one area of concern about use of antioxidant phytonutrients is how much suppression of oxidation may be compatible with good health, as toxic free radicals are required for defence mechanisms. These food-health concepts would probably spur the large-scale oil palm (and monoculture) plantations, which are already seen to be a major cause of deforestation and replacement of diverse ecosystems in many countries. However, the environmental advantages of palm phytonutrients are that they are prepared from the readily available raw material from palm oil milling processes. Palm fruit, one of only a few fatty fruits, is likely to have an increasingly substantiated place in human health, not only through the provision of acceptable dietary fats, but also its characteristic protective phytonutrients.
The palm fruit (Elaies guineensis) yields palm oil, a palmitic-oleic rich semi solid fat and the fat-soluble minor components, vitamin E (tocopherols,tocotrienols), carotenoids and phytosterols. A recent innovation has led to the recovery and concentration of water-soluble antioxidants from palm oil milling waste, characterized by its high content of phenolic acids and flavonoids. These natural ingredients pose both challenges and opportunities for the food and nutraceutical industries. Palm oil’s rich content of saturated and monounsaturated fatty acids has actually been turned into an asset in view of current dietary recommendations aimed at zero trans content in solid fats such as margarine, shortenings and frying fats. Using palm oil in combination with other oils and fats facilitates the development of a new generation of fat products that can be tailored to meet most current dietary recommendations. The wide range of natural palm oil fractions, differing in their physico-chemical characteristics, the most notable of which is the carotenoid-rich red palm oil further assists this. Palm vitamin E (30% tocopherols, 70% tocotrienols) has been extensively researched for its nutritional and health properties, including antioxidant activities, cholesterol lowering, anti-cancer effects and protection against atherosclerosis. These are attributed largely to its tocotrienol content. A relatively new output from the oil palm fruit is the water-soluble phenolic-flavonoid-rich antioxidant complex. This has potent antioxidant properties coupled with beneficial effects against skin, breast and other cancers. Enabled by its water solubility, this is currently being tested for use as nutraceuticals and in cosmetics with potential benefits against skin aging. A further challenge would be to package all these palm ingredients into a single functional food for better nutrition and health.
Background: The uptake and biotransformation of γ-tocopherol (γ-T) in humans is largely unknown. Using a stable isotope method we investigated these aspects of γ-T biology in healthy volunteers and their response to r-T supplementation.
Method: A single bolus of 100mg of deuterium labeled γ-T acetate (d2-γ-TAC, 94% isotopic purity) was administered with a standard meal to 21 healthy subjects. Blood and urine (first morning void) were collected at baseline and a range of time points between 6 and 240h post-supplementation. The concentrations of d2 and d0-γ-T in plasma and its major metabolite 2,7,8-trimethyl-2-(b-carboxyethyl)-6-hydroxychroman (γ-CEHC) in plasma and urine were measured by GC-MS. In two subjects, the total urine volume was collected for 72h post supplementation. The effects of γ-T supplementation on a- concentrations in plasma and α-T and γ-T metabolite formation were also assessed by HPLC or GC-MS analysis.
Results: At baseline, mean plasma α-T concentration was approximately 15 times higher than γ-T (28.3 vs 1.9µmol/l). In contrast, plasma γ-CEHC concentration (0.191µmol/l) was 12 fold greater than α-CEHC (0.016µmol/l) while in urine it was 3.5 fold lower (0.82 and 2.87 µmol, respectively) suggesting that the clearance of α-CEHC from plasma was more than 40 times that of γ-CEHC. After d2-γ-TAC administration, the d2 forms of γ-T and γ-CEHC in plasma and urine increased ,but with markedly inter-individual variability, while the d0 species were hardy affected. Mean total concentrations of γ-T and γ-CEHC in plasma peaked, respectively, between 0-9, 6-12 and 9-24h post supplementation with increases over baseline levels of 6-14 fold. All these parameters returned to baseline by 72h. following challenge, the total urinary excretion of d2-γ-T equivalents was approximately 7mg. Baseline levels of γ-T correlated positively with the post-supplementation rise of (d0 + d2) –γ-T and γ-CEHC level in plasma, but correlated negatively with urinary levels of (d0+d2)-γ-CEHC. Supplementation with 100mg γ-TAC had minimal influence on plasma concentrations of α-T and α-T related metabolite formation and excretion.
Conclusion: Ingestion of 100mg of γ-TA transiently increases plasma concentrations of r-T as it undergoes sustained catabolism to CEHC without markedly influencing the pre-existing plasma pool of γ-T nor the concentration and metabolism of α-T. These pathways appear tightly regulated, most probably to keep high steady-state blood ratios α-T to γ-T and γ-CEHC to α-CEHC.
Alpha-tocopherol transfer protein (alpha-TTP) is a liver protein responsible for the selective retention of alpha-tocopherol from dietary vitamin E, which is a mixture of alpha, beta, gamma, and delta-tocopherols and the corresponding tocotrienols. The alpha-TTP-mediated transfer of alpha-tocopherol into nascent VLDL is the major determinant of plasma alpha-tocopherol levels in humans. Mutations in the alpha-TTP gene have been detected in patients suffering from low plasma alpha-tocopherol and ataxia with isolated vitamin E deficiency (AVED). The crystal structure of alpha-TTP reveals two conformations. In its closed tocopherol-charged form, a mobile helical surface segment seals the hydrophobic binding pocket. In the presence of detergents, an open conformation is observed, which probably represents the membrane-bound form. The selectivity of alpha-TTP for RRR-alpha-tocopherol is explained from the van der Waals contacts occurring in the lipid-binding pocket. Mapping the known mutations leading to AVED onto the crystal structure shows that no mutations occur directly in the binding pocket.
2,7,8-Trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), a metabolite of gamma-tocopherol and gamma-tocotrienol, was identified as a new endogenous natriuretic factor. However, gamma-tocopherol and gamma-tocotrienol, both precursors of gamma-CEHC, have never directly been observed to have natriuretic potency. Thus, we investigated whether gamma-tocotrienol could cause natriuresis and diuresis in rats. The rats were divided into two groups that were given a control or a high-sodium diet for 4 weeks, and then subdivided into placebo and gamma-tocotrienol subgroups given only corn oil-removed vitamin E and oil supplemented with gamma-tocotrienol, respectively. After oral administration of three experimental doses, rat urine was collected and gamma-CEHC, urine volume, sodium, and potassium content were determined. Only in rats given a high-NaCl diet did gamma-tocotrienol accelerate and increase sodium excretion, showing no effect on potassium excretion. Sodium excretion in the high-NaCl group given gamma-tocotrienol was 5.06 +/- 2.70 g/day, and in the control group given gamma-tocotrienol, 0.11 +/- 0.06 g/day. Furthermore, gamma-tocotrienol affected urine volume in the specific condition of high-NaCl body stores and gamma-tocotrienol supplementation. In this study, we found that gamma-tocotrienol, one of the natural vitamin E homologs, stimulates sodium excretion in vivo, suggesting that gamma-tocotrienol possesses a hormone-like natriuretic function.
The eight vitamers of vitamin E (alpha-, beta-, gamma-, and delta-tocopherols and -tocotrienols) have different antioxidant and biological activities and have different distributions in foods. Some cereals, especially oat, rye, and barley, are good sources of tocotrienols. A fast procedure for the determination of tocopherols and tocotrienols (tocols) in cereal foods was developed. It involves sample saponification and extraction followed by normal phase high-performance liquid chromatography (HPLC). The results have been compared with those found by direct extraction without saponification. The method is sensitive and selective enough to be tested on a wide variety of cereal samples. The highest tocol levels were found in soft wheat and barley ( approximately 75 mg/kg of dry weight). beta-Tocotrienol is the main vitamer found in hulled and dehulled wheats (from 33 to 43 mg/kg of dry weight), gamma-tocopherol predominates in maize (45 mg/kg of dry weight) ), and alpha-tocotrienol predominates in oat and barley (56 and 40 mg/kg of dry weight, respectively).
Tocopherols and tocotrienols are metabolized by side chain degradation initiated by cytochrome P450 (CYP)-catalyzed omega-hydroxylation followed by beta-oxidation. Whereas alpha-tocopherol is only poorly metabolized, high amounts of the final products, carboxyethyl hydroxychroman (CEHC), are found from other tocols in HepG2 cells and in human urine. CYP3A4 and CYP4F2 were suggested to be involved in tocopherol degradation. CYP3A4 metabolizes most of the drugs and is induced by many of its substrates via the activation of the pregnane X receptor (PXR). Also tocopherols and in particular tocotrienols induce the expression of a PXR-driven reporter gene and the expression of endogenous CYP3A4 and CYP3A5 which is supported by sporadic publications spread over the last 30 years. The potential interference of vitamin E with drug metabolism is discussed in the light of related complications evoked by herbal remedies.
Reactive oxygen species and various electrophiles are involved in the etiology of diseases varying from cancer to cardiovascular and pulmonary disorders. The human body is protected against damaging effects of these compounds by a wide variety of systems. An important line of defense is formed by antioxidants. Vitamin E (consisting of various forms of tocopherols and tocotrienols) is an important fat-soluble, chain-breaking antioxidant. Besides working as an antioxidant, this compound possesses other functions with possible physiological relevance. The glutathione-dependent enzymes form another line of defense. Two important enzymes in this class are the free radical reductase and glutathione S-transferases (GSTs). The GSTs are a family of phase II detoxification enzymes. They can catalyze glutathione conjugation with various electrophiles. In most cases the electrophiles are detoxified by this conjugation, but in some cases the electrophiles are activated. Antioxidants do not act in isolation but form an intricate network. It is, for instance, known that vitamin E, together with glutathione (GSH) and a membrane-bound heat labile GSH-dependent factor, presumably an enzyme, can prevent damaging effects of reactive oxygen species on polyunsaturated fatty acids in biomembranes (lipid peroxidation). This manuscript reviews the interaction between the two defense systems, vitamin E and glutathione-dependent enzymes. On the simplest level, antioxidants such as vitamin E have protective effects on glutathione-dependent enzymes; however, we will see that reality is somewhat more complicated.
Dietary antioxidants play a major role in maintaining the homeostasis of the oxidative balance. They are believed to protect humans from disease and aging. Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and other micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. This article addresses data provided from clinical trials, highlighting the clinical pharmacokinetics of vitamin C, vitamin E, beta-carotene, lycopene, lutein, quercetin, rutin, catechins and selenium. The bioavailability of vitamin C is dose-dependent. Saturation of transport occurs with dosages of 200-400 mg/day. Vitamin C is not protein-bound and is eliminated with an elimination half-life (t((1/2))) of 10 hours. In Western populations plasma vitamin C concentrations range from 54-91 micro mol/L. Serum alpha- and gamma-tocopherol range from 21 micro mol/L (North America) to 27 micro mol/L (Europe) and from 3.1 micro mol/L to 1.5 micro mol/L, respectively. alpha-Tocopherol is the most abundant tocopherol in human tissue. The bioavailability of all-rac-alpha-tocopherol is estimated to be 50% of R,R,R-alpha-tocopherol. The hepatic alpha-tocopherol transfer protein (alpha-TTP) together with the tocopherol-associated proteins (TAP) are responsbile for the endogenous accumulation of natural alpha-tocopherol. Elimination of alpha-tocopherol takes several days with a t((1/2)) of 81 and 73 hours for R,R,R-alpha-tocopherol and all-rac-alpha-tocopherol, respectively. The t((1/2)) of tocotrienols is short, ranging from 3.8-4.4 hours for gamma- and alpha-tocotrienol, respectively. gamma-Tocopherol is degraded to 2, 7, 8-trimethyl-2-(beta-carboxyl)-6-hyrdoxychroman by the liver prior to renal elimination. Blood serum carotenoids in Western populations range from 0.28-0.52 micro mol/L for beta-carotene, from 0.2-0.28 for lutein, and from 0.29-0.60 for lycopene. All-trans-carotenoids have a better bioavailability than the 9-cis-forms. Elimination of carotenoids takes several days with a t((1/2)) of 5-7 and 2-3 days for beta-carotene and lycopene, respectively. The bioconversion of beta-carotene to retinal is dose-dependent, and ranges between 27% and 2% for a 6 and 126mg dose, respectively. Several oxidised metabolites of carotenoids are known. Flavonols such as quercetin glycosides and rutin are predominantly absorbed as aglycones, bound to plasma proteins and subsequently conjugated to glucuronide, sulfate, and methyl moieties. The t((1/2)) ranges from 12-19 hours. The bioavailabillity of catechins is low and they are eliminated with a t((1/2)) of 2-4 hours. Catechins are degraded to several gamma-valerolactone derivatives and phase II conjugates have also been identified. Only limited clinical pharmacokinetic data for other polyphenols such as resveratrol have been reported to date.