Vitamins E and C, beta-carotene, and other carotenoids as antioxidants

Sies H, Stahl W.

Am J Clin Nutr. 1995 Dec;62(6 Suppl):1315S-1321S.

Tocopherols and tocotrienols (vitamin E), ascorbic acid (vitamin C), and the carotenoids react with free radicals, notably peroxyl radicals, and with singlet molecular oxygen (1O2), which is the basis for their function as antioxidants. RRR-alpha-Tocopherol is the major peroxyl radical scavenger in biological lipid phases such as membranes or low-density lipoproteins. Ascorbic acid is present in aqueous compartments (eg, cytosol, plasma, and other body fluids) and can reduce the tocopherol radical; it also has several metabolically important cofactor functions in enzyme reactions, especially hydroxylations. These micronutrients need to be regenerated on oxidation in the biological setting, hence the need for further coupling to nonradical reducing systems such as glutathione-glutathione disulfide, dihydrolipoate-lipoate, or NADPH-NADP+ and NADH-NAD+. Carotenoids, such as beta-carotene, lycopene, and some oxycarotenoids, eg, zeaxanthin and lutein, exert antioxidant functions in lipid phases by quenching 1O2 or free radicals. There are pronounced differences in tissue carotenoid patterns, extending also to the distribution between the all-trans and various cis isomers of the respective carotenoids. Physical quenching leaves the structure intact, so that in this mode the carotenoids do not require a regeneration reaction.

Tocotrienols from palm oil as potent inhibitors of lipid peroxidation and protein oxidation in rat brain mitochondria

Kamat JP, Devasagayam TP.

Neurosci Lett. 1995 Aug 11;195(3):179-82.

The tocotrienol-rich-fraction (TRF) from palm oil, being tried as a more economical and efficient substitute for alpha-tocopherol, significantly inhibited oxidative damage in vitro to both lipids and proteins in rat brain mitochondria induced by ascorbate-Fe2+, the free radical initiator azobis(2-amidopropane)dihydrochloride (AAPH) and photosensitisation. The observed inhibitory effect was both time- and concentration-dependent. At a low concentration of 5 microM, TRF can significantly inhibit oxidative damage to both lipids and proteins. The inhibitory effect of TRF seems to be mainly due to gamma-tocotrienol and to a lesser extent alpha- and delta-tocotrienols. TRF was significantly more effective than alpha-tocopherol. This fraction from palm oil can be considered a natural antioxidant supplement capable of protecting the brain against oxidative damage and thereby from the ensuing adverse alterations.

Coupling the cholesterol- and tumor-suppressive actions of palm oil to the impact of its minor constituents on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity

Elson CE, Qureshi AA.

Prostaglandins Leukot Essent Fatty Acids. 1995 Feb;52(2-3):205-7.

The impact of palm oil on cardiovascular disease and cancer may be explained by the mevalonate-suppressive action of constituent isoprenoid end products of plant secondary metabolism. Assorted monoterpenes, sesquiterpenes, carotenoids and tocotrienols down regulate, post-transcriptionally, 3-hydroxy-3-methylglutaryl coenzyme A reductase activity thereby modestly decreasing cholesterol synthesis and concomitantly decreasing LDL cholesterol. The reductase activity in tumor tissues differs from that of liver in being resistant to sterol feedback regulation. Tumor reductase activity retains sensitivity to the post-transcriptional regulation. As a consequence, the isoprenoid-mediated suppression of mevalonate synthesis depletes tumor tissues of two intermediate products, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are incorporated post-translationally into growth control-associated proteins.

Protection by tocotrienols against hypercholesterolaemia and atheroma

Teoh MK, Chong JM, Mohamed J, Phang KS.

Med J Malaysia. 1994 Sep;49(3):255-62.

Antioxidants such as tocotrienols may protect against atherosclerosis since tissue injury from free radicals is a final common pathway of damage in arterial disease. In this study, the effects of tocotrienols on serum cholesterol, lipid peroxides, and aorta atheroma were assessed in rabbits fed an atherogenic diet for 12 weeks. Tocotrienols were more effective than tocopherols in preventing increases in serum LDL (p = 0.03) and total cholesterol (p = 0.008) levels in the cholesterol-fed rabbits. Elevation of serum lipid peroxides was effectively suppressed by tocotrienols (p = 0.01). Both tocopherols and tocotrienols offered significant protection against atheroma in the rabbit aorta, but tocotrienols had a stronger hypolipidaemic effect.

The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables

Elson CE, Yu SG.

J Nutr. 1994 May;124(5):607-14.

Anutritive isoprenoid constituents of fruits, vegetables, cereal grains and essential oils exhibit a spectrum of anticarcinogenic activities. The induction of hepatic Phase II detoxifying activities by dietary isoprenoids appears to underlie their blocking action. The second anticarcinogenic action of the dietary isoprenoids, suppression of the growth of chemically initiated and transplanted tumors is, we suggest, secondary to the inhibition of mevalonate pathway activities. Mevinolin, a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase activity, depletes cells of the intermediate products of the pathway that are required for the posttranslational modification of proteins, a process giving the proteins lipophilic anchors that bind to membranes. As a consequence, nuclear lamins and ras oncoproteins remain in nascent states, and cells do not proliferate. gamma-Tocotrienol, perillyl alcohol, geraniol and d-limonene suppress hepatic HMG-CoA reductase activity, a rate-limiting step in cholesterol synthesis, and modestly lower serum-cholesterol levels of animals. These isoprenoids also suppress tumor growth. The HMG-CoA reductase of neoplastic tissues differs from that of sterologenic tissues in being markedly resistant to sterol feedback inhibition. Our review suggests that the mevalonate pathway of tumor tissues is uniquely sensitive to the inhibitory actions of the dietary isoprenoids.

Inhibition of tumour promotion by various palm-oil tocotrienols

Goh SH, Hew NF, Norhanom AW, Yadav M.

Int J Cancer. 1994 May 15;57(4):529-31.

Inhibition of tumour promotion by various vitamin E compounds (tocopherols and tocotrienols) and some of their dimers was examined by an in vitro assay utilizing the activation of Epstein-Barr virus (EBV) early antigen (EA) expression in EBV-genome-carrying human lymphoblastoid cells. The results reveal that gamma- and delta-tocotrienols derived from palm oil exhibit a strong activity against tumour promotion by inhibiting EBV EA expression in Raji cells induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). However, alpha- and gamma-tocopherols and dimers of gamma-tocotrienol or gamma-tocopherol lack this activity.

Vitamin E, glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured hepatocytes of rats treated with carcinogens

Ong FB, Wan Ngah WZ, Top AG, Khalid BA, Shamaan NA.

Int J Biochem. 1994 Mar;26(3):397-402.

1. The effects of alpha-tocopherol and gamma-tocotrienol on glutathione S-transferase (GST) and gamma-glutamyl transpeptidase (gamma-GT) activities in cultured hepatocytes prepared from rats treated with diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) were investigated. 2. Both the alpha-tocopherol and gamma-tocotrienol treated hepatocytes showed significantly higher (P < 0.05) GST activities than untreated hepatocytes prepared from the carcinogen treated rats in the first 3 days of culture. Treatment with alpha-tocopherol and gamma-tocotrienol generally resulted in a tendency to increase the GST activities above that in the untreated hepatocytes. 3. Treatment with high doses (125-250 microM) of alpha-tocopherol and low doses (12.5-25 microM) of gamma-tocotrienol generally resulted in a significant reduction in gamma-GT activities at 1-3 days. gamma-GT activities are reduced as the dose of alpha-tocopherol and gamma-tocotrienol are increased.

Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols

Pearce BC, Parker RA, Deason ME, Dischino DD, Gillespie E, Qureshi AA, Volk K, Wright JJ.

J Med Chem. 1994 Feb 18;37(4):526-41.

Tocotrienols exhibit antioxidant and cholesterol-biosynthesis-inhibitory activities and may be of value as antiatherosclerotic agents. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase (HMGR) in a manner mimicking the action of putative non-sterol feedback inhibitors. The in vitro cholesterol-biosynthesis-inhibitory and HMGR-suppressive activities in HepG2 cells of an expanded series of benzopyran and tetrahydronaphthalene isosteres and the hypocholesterolemic activity of selected compounds assessed in orally dosed chickens are presented. Preliminary antioxidant data of these compounds have been obtained using cyclic voltammetry and Cu-induced LDL oxidation assays. The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol deliver a high level of HMGR suppression, unsurpassed by synthetic analogues of the present study. In orally dosed chickens, 8-bromotocotrienol (4o), 2-desmethyltocotrienol (4t), and the tetrahydronaphthalene derivative 35 exhibit a greater degree of LDL cholesterol lowering than the natural tocotrienols.

Gamma-Tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets

Watkins T, Lenz P, Gapor A, Struck M, Tomeo A, Bierenbaum M.

Lipids. 1993 Dec;28(12):1113-8.

This study was designed to determine whether incorporation of gamma-tocotrienol or alpha-tocopherol in an atherogenic diet would reduce the concentration of plasma cholesterol, triglycerides and fatty acid peroxides, and attenuate platelet aggregability in rats. For six weeks, male Wistar rats (n = 90) were fed AIN76A semisynthetic test diets containing cholesterol (2% by weight), providing fat as partially hydrogenated soybean oil (20% by weight), menhaden oil (20%) or corn oil (2%). Feeding the ration with menhaden oil resulted in the highest concentrations of plasma cholesterol, low and very low density lipoprotein cholesterol, triglycerides, thiobarbituric acid reactive substances and fatty acid hydroperoxides. Consumption of the ration containing gamma-tocotrienol (50 mg/kg) and alpha-tocopherol (500 mg/kg) for six weeks led to decreased plasma lipid concentrations. Plasma cholesterol, low and very low density lipoprotein cholesterol, and triglycerides each decreased significantly (P < 0.001). Plasma thiobarbituric acid reactive substances decreased significantly (P < 0.01), as did the fatty acid hydroperoxides (P < 0.05), when the diet contained both chromanols. Supplementation with gamma-tocotrienol resulted in similar, though quantitatively smaller, decrements in these plasma values. Plasma alpha-tocopherol concentrations were lowest in rats fed menhaden oil without either chromanol. Though plasma alpha-tocopherol did not rise with gamma-tocotrienol supplementation at 50 mg/kg, gamma-tocotrienol at 100 mg/kg of ration spared plasma alpha-tocopherol, which rose from 0.60 +/- 0.2 to 1.34 +/- 0.4 mg/dL (P < 0.05). The highest concentration of alpha-tocopherol was measured in plasma of animals fed a ration supplemented with alpha-tocopherol at 500 mg/kg.

Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: Implication to the molecular mechanism of their antioxidant potency

Suzuki YJ, Tsuchiya M, Wassall SR, Choo YM, Govil G, Kagan VE, Packer L.

Biochemistry. 1993 Oct 12;32(40):10692-9.

d-alpha-Tocopherol and d-alpha-tocotrienol are two vitamin E constituents having the same aromatic chromanol “head” but different hydrocarbon “tails”. alpha-Tocotrienol has been shown to be more potent in protecting against free radical-induced oxidative stress than alpha-tocopherol. Simple models of phospholipid membrane systems were used to investigate the mechanism of the antioxidant potency of alpha-tocotrienol in terms of its effects on membrane order and reorientation dynamics. Chemiluminescence and fluorescence measurements demonstrated that alpha-tocotrienol exhibits significantly greater peroxyl radical scavenging potency than alpha-tocopherol in phosphatidylcholine liposomes, whereas both antioxidants have identical activity in hexane. This suggests that the antioxidant potency of alpha-tocotrienol requires the membrane environment. When alpha-tocopherol and alpha-tocotrienol were examined for their effects on phospholipid molecular order using conventional ESR spin labeling with 5- and 16-position-labeled doxylstearic acid, although both vitamin E constituents disordered the gel phase and stabilized the liquid-crystalline phase, no differences were observed between the effects of the two compounds. A slightly greater increase (19% vs 15%) in ordering of the liquid-crystalline state due to alpha-tocopherol, however, was discerned in noninvasive 2H NMR experiments. The difference is most noticeable near C10-C13 positions of the phospholipid chain, possibly suggesting alpha-tocotrienol is located closer to the membrane surface. Saturation-transfer ESR, furthermore, revealed that on the time scale tau c = 10(-7)-10(-3) s the rates of rotation about the long molecular axis and of the wobbling motion of the axis are modified to differing extents by the two forms of the vitamin E

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