With the aim to enhance the plant vitamin E content, the barley gene encoding 4-hydroxyphenylpyruvate dioxygenase was overexpressed in tobacco plants under control of the 35S promoter. Transgenic lines have a higher capacity for homogentisate biosynthesis as evident by a more than 10-fold higher resistance towards the bleaching herbicide sulcotrione. Seeds from transgenic lines have an up to two-fold enhanced level of vitamin E without a change in the ratio of gamma-tocopherol and gamma-tocotrienol. While the vitamin E content is not affected in leaves, the level of plastoquinone is enhanced in leaves of transgenic lines during leaf senescence.
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We previously showed that alpha- and gamma-tocotrienols accumulate in adipose tissue and skin but not in plasma or other tissues of rats fed a tocotrienol-rich fraction extracted from palm oil containing alpha-tocopherol and alpha- and gamma-tocotrienols. To clarify the nature of tocotrienol metabolism, we studied the distribution of alpha- or gamma-tocotrienol in rats fed alpha- or gamma-tocotrienol without alpha-tocopherol, and the effect of alpha-tocopherol on their distribution. Wistar rats (4-wk-old) were fed a diet with 50 mg alpha-tocotrienol/kg alone or with 50 mg alpha-tocopherol/kg in expt. 1, and a diet with 50 mg gamma-tocotrienol/kg alone or with 50 mg alpha-tocopherol/kg in expt. 2, for 8 wk. alpha-Tocotrienol was detected in various tissues and plasma of the rats fed alpha-tocotrienol alone, and the alpha-tocotrienol concentrations in those tissues and plasma decreased (P < 0.05) by the dietary alpha-tocopherol in the rats fed alpha-tocotrienol with alpha-tocopherol. However, gamma-tocotrienol preferentially accumulated in the adipose tissue and skin of the rats fed gamma-tocotrienol alone, and the dietary alpha-tocopherol failed either to decrease (P >/= 0.05) gamma-tocotrienol concentrations in the adipose tissue and skin or to increase (P >/= 0.05) in the urinary excretion of 2,7,8-trimethyl-2(2′-carboxymethyl)-6-hydroxycroman, a metabolite of gamma-tocotrienol, in the rats fed gamma-tocotrienol with alpha-tocopherol. These data suggest that alpha-tocopherol enhances the alpha-tocotrienol metabolism but not the gamma-tocotrienol metabolism in rats.
A study was conducted to evaluate the bioavailability of α, γ and δ tocotrienols administered via oral, intravenous, intramuscular and intraperitoneal routes in rats. Three separate experiments, each conducted according to a two-way crossover design, were carried out to compare intravenous and oral, intramuscular and oral, and intraperitoneal and oral administration. Oral absorption of all three tocotrienols was found to be incomplete. Of the three tocotrienols, α-tocotrienol had the highest oral bioavailability, at about 27.7± 9.2%, compared with γ- and δ-tocotrienols, which had values of 9.1± 2.4% and 8.5±3.5%, respectively. Such biodiscrimination was also observed in their total clearance rates (estimated from the intravenous data). -Tocotrienol showed the lowest clearance rate at about 0.16 L kg 1 h 1, whereas that of δ- and γ-tocotrienols was quite similar, with values of 0.24 and 0.23 L kg 1 h 1, respectively. Interestingly, all three tocotrienols were found to be negligibly absorbed when administered intraperitoneally and intramuscularly. Thus, these two routes of administration should be avoided when evaluating the biological activities of the tocotrienols in whole animal experiments.
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.
This study examined the effects of a tocotrienol-rich fraction (TRF) obtained from palm oil on the healing of aspirin-induced gastric mucosal lesions. Thirty-six male Sprague-Dawley rats (200-250 g) were randomly divided into three groups. Group I was fed a vitamin E-deficient diet (control), Group II was fed a vitamin E-deficient diet supplemented with tocopherol (300 mg/kg food) and Group III was fed a vitamin E-deficient diet supplemented with TRF (300 mg/kg food). After eight weeks, the control and treated groups received a single intragastric dose of 400 mg/kg body weight aspirin. The rats were killed 24 h after exposure to aspirin. Assessment of gastric lesions showed a lower gastric lesion index in the TRF (P = 0.0005) and tocopherol groups (P = 0.0008) compared to the control. The gastric malondialdehyde (MDA) content was also lower in the TRF (P = 0.025) and tocopherol groups (P = 0.025) compared to control. There were, however, no significant differences in the gastric lesion index and gastric MDA content between the TRF and tocopherol-fed groups. There were no significant differences in the adherent gastric mucous concentration and gastric acid concentration among all groups. We conclude that the TRF and tocopherol are equally effective in preventing aspirin-induced gastric lesions. The most probable mechanism is through their ability to limit lipid peroxidation, which is involved in aspirin-induced gastric lesions.
In this study the effects of vitamin E deficiency and supplementation on bone calcification were determined using 4-month-old female Sprague-Dawley rats. The rats weighed between 180 and 200 g. The study was divided in three parts. In experiment I the rats were given normal rat chow (RC, control group), a vitamin E deficient (VED) diet or a 50% vitamin E deficient (50%VED) diet. In experiment 2 the rats were given VED supplemented with 30 mg/kg palm vitamin E (PVE30), 60 mg/kg palm vitamin E (PVE60) or 30 mg/kg pure alpha-tocopherol (ATF). In experiment 3 the rats were fed RC and given the same supplements as in experiment 2. The treatment lasted 8 months. Vitamin E derived from palm oil contained a mixture of ATF andtocotrienols. Rats on the VED and 50%VED diets had lower bone calcium content in the left femur compared to the RC group (91.6 +/- 13.3 mg and 118.3 +/- 26.0 mg cf 165.7 +/- 15.2 mg; P < 0.05) and L5 vertebra (28.3 +/- 4.0 mg and 39.5 +/- 6.2 mg compared with 51.4 +/- 5.8 mg; P < 0.05). Supplementing the VED group with PVE60 improved bone calcification in the left femur (133.6 +/- 5.0 mg compared with 91.6 +/- 13.3 mg; P < 0.05) and L5 vertebra (41.3 +/- 3.3 mg compared with 28.3 +/- 4.0 mg; P < 0.05) while supplementation with PVE30 improved bone calcium content in the L5 vertebra (35.6 +/- 3.1 mg compared with 28.3 +/- 4.0 mg; P < 0.05). However, supplementation with ATF did not change the lumbar and femoral bone calcium content compared to the VED group. Supplementing the RC group with PVE30, PVE60 or ATF did not cause any significant changes in bone calcium content. In conclusion, vitamin E deficiency impaired bone calcification. Supplementation with the higher dose of palm vitamin E improved bone calcium content, but supplementation with pure ATF alone did not. This effect may be attributed to the tocotrienol content of palm vitamin E. Therefore, tocotrienols play an important role in bone calcification.
Cardiovascular disease, in particular coronary artery disease (CAD), remains the most important cause of morbidity and mortality in developed countries and, in the near future, more so in the developing world. Atherosclerotic plaque formation is the underlying basis for CAD. Growth of the plaque leads to coronary stenosis, causing a progressive decrease in blood flow that results in angina pectoris. Acute myocardial infarction and unstable angina were recently recognised as related to plaque rupture, not progressive coronary stenosis. Acute thrombus formation causes an abrupt coronary occlusion. The characteristics of the fibrin cap, contents of the plaque, rheological factors and active inflammation within the plaque contribute to plaque rupture. Oxidative processes are important in plaque formation. Oxidized low density lipoproteins (LDL) but not unoxidized LDL is engulfed by resident intimal macrophages, transforming them into foam cells which develop into fatty streaks, the precursors of the atherosclerotic plaque. Inflammation is important both in plaque formation and rupture. Animal studies have shown that antioxidants reduce plaque formation and lead to plaque stabilisation. In humans, high intakes of antioxidants are associated with lower incidence of CAD, despite high serum cholesterol levels. This observation suggests a role for inflammation in CAD and that reducing inflammation using antioxidants may ameliorate these processes. Men and women with high intakes of vitamin E were found to have less CAD. Vitamin E supplementation was associated with a significant reduction in myocardial infarction and cardiovascular events in the incidence of recurrent myocardial infarction. In the hierarchy of evidence in evidence-based medicine, data from large placebo-controlled clinical trials is considered necessary. Results from various mega-trials have not shown benefits (nor adverse effects) conferred by vitamin E supplementation, suggesting that vitamin E has no role in the treatment of CAD. These results do not seem to confirm, at the clinical level, the effect of antioxidants against active inflammation during plaque rupture. However, a closer examination of these studies showed a number of limitations, rendering them inconclusive in addressing the role of vitamin E in CAD prevention and treatment. Further studies that specifically address the issue of vitamin E in the pathogenesis of atherosclerosis and in the treatment of CAD need be performed. These studies should use the more potent antioxidant property of alpha-tocotrienol vitamin E.
Vitamin E, the most important lipid-soluble antioxidant, was discovered at the University of California at Berkeley in 1922. Since its discovery, studies of the constituent tocopherols and tocotrienols have focused mainly on their antioxidant properties. In 1991 Angelo Azzi’s group (Boscoboinik et al. 1991a,b) first described non-antioxidant cell signalling functions for alpha-tocopherol, demonstrating that vitamin E regulates protein kinase C activity in smooth muscle cells. At the transcriptional level, alpha-tocopherol modulates the expression of the hepatic alpha-tocopherol transfer protein, as well as the expression of liver collagen alphal gene, collagenase gene and alpha-tropomyosin gene. Recently, a tocopherol-dependent transcription factor (tocopherol-associated protein) has been discovered. In cultured cells it has been demonstrated that vitamin E inhibits inflammation, cell adhesion, platelet aggregation and smooth muscle cell proliferation. Recent advances in molecular biology and genomic techniques have led to the discovery of novel vitamin E-sensitive genes and signal transduction pathways.