Vitamin E inhibits protein oxidation in skeletal muscle of resting and exercised rats

Reznick AZ, Witt E, Matsumoto M, Packer L.

Biochem Biophys Res Commun. 1992 Dec 15;189(2):801-6.

It is well known that exercise induces lipid peroxidation in skeletal muscle and that vitamin E prevents exercise-induced lipid damage. In this study we show for the first time, an increase in protein oxidation in skeletal muscle after a single bout of exercise, related to an exercise-induced decrease in lipophilic antioxidants, and substantial protection against both resting and exercise-induced protein oxidation by supplementation with various isomers (alpha-tocopherol, alpha-tocotrienol) of vitamin E.

Hypocholesterolemic activity of synthetic and natural tocotrienols

Pearce BC, Parker RA, Deason ME, Qureshi AA, Wright JJ.

J Med Chem. 1992 Oct 2;35(20):3595-606.

Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.

Antioxidant functions of vitamins. Vitamins E and C, beta-carotene, and other carotenoids

Sies H, Stahl W, Sundquist AR.

Ann N Y Acad Sci. 1992 Sep 30;669:7-20

Tocopherols and tocotrienols (vitamin E) and ascorbic acid (vitamin C) as well as the carotenoids react with free radicals, notably peroxyl radicals, and with singlet molecular oxygen (1O2), this being the basis of their function as antioxidants. RRR-alpha-tocopherol is the major peroxyl radical scavenger in biological lipid phases such as membranes or low-density lipoproteins (LDL). L-Ascorbate is present in aqueous compartments (e.g. cytosol, plasma, and other body fluids) and can reduce the tocopheroxyl radical; it also has a number of metabolically important cofactor functions in enzyme reactions, notably hydroxylations. Upon oxidation, these micronutrients need to be regenerated 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, notably beta-carotene and lycopene as well as oxycarotenoids (e.g. zeaxanthin and lutein), exert antioxidant functions in lipid phases by free-radical or 1O2 quenching. 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. Antioxidant functions are associated with lowering DNA damage, malignant transformation, and other parameters of cell damage in vitro as well as epidemiologically with lowered incidence of certain types of cancer and degenerative diseases, such as ischemic heart disease and cataract. They are of importance in the process of aging. Reactive oxygen species occur in tissues and cells and can damage DNA, proteins, carbohydrates, and lipids. These potentially deleterious reactions are controlled in part by antioxidants that eliminate prooxidants and scavenge free radicals. Their ability as antioxidants to quench radicals and 1O2 may explain some anticancer properties of the carotenoids independent of their provitamin A activity, but other functions may play a role as well. Tocopherols are the most abundant and efficient scavengers of peroxyl radicals in biological membranes. The water-soluble antioxidant vitamin C can reduce tocopheroxyl radicals directly or indirectly and thus support the antioxidant activity of vitamin E; such functions can be performed also by other appropriate reducing compounds such as glutathione (GSH) or dihydrolipoate. The biological efficacy of the antioxidants is also determined by their biokinetics.

Interactions among antioxidants in health and disease: Vitamin E and its redox cycle

Packer L.

Proc Soc Exp Biol Med. 1992 Jun;200(2):271-6.

Probably most diseases at some point during their course involve free radical reactions in tissue injury. In some cases, free radical reactions may be involved in multiple sites and at different stages of a chronic disease. So, both acute and degenerative diseases are thought to involve free radical reactions in tissue injury. An overview will be given of the evidence for the occurrence of free radicals and the importance of antioxidant interventions, with particular reference to the lipophilic antioxidant vitamin E (tocopherols and tocotrienols).

Recycling of vitamin E in human low density lipoproteins

Kagan VE, Serbinova EA, Forte T, Scita G, Packer L.

J Lipid Res. 1992 Mar;33(3):385-97.

Oxidative modification of low density lipoproteins (LDL) and their unrestricted scavenger receptor-dependent uptake is believed to account for cholesterol deposition in macrophage-derived foam cells. It has been suggested that vitamin E that is transported by LDL plays a critical role in protecting against LDL oxidation. We hypothesize that the maintenance of sufficiently high vitamin E concentrations in LDL can be achieved by reducing its chromanoxyl radicals, i.e., by vitamin E recycling. In this study we demonstrate that: i) chromanoxyl radicals of endogenous vitamin E and of exogenously added alpha-tocotrienol, alpha-tocopherol or its synthetic homologue with a 6-carbon side-chain, chromanol-alpha-C6, can be directly generated in human LDL by ultraviolet (UV) light, or by interaction with peroxyl radicals produced either by an enzymic oxidation system (lipoxygenase + linolenic acid) or by an azo-initiator, 2,2′-azo-bis(2,4-dimethylvaleronitrile) (AMVN; ii) ascorbate can recycle endogenous vitamin E and exogenously added chromanols by direct reduction of chromanoxyl radicals in LDL; iii) dihydrolipoic acid is not efficient in direct reduction of chromanoxyl radicals but recycles vitamin E by synergistically interacting with ascorbate (reduces dehydroascorbate thus maintaining the steady-state concentration of ascorbate); and iv) beta-carotene is not active in vitamin E recycling but may itself be protected against oxidative destruction by the reductants of chromanoxyl radicals. We suggest that the recycling of vitamin E and other phenolic antioxidants by plasma reductants may be an important mechanism for the enhanced antioxidant protection of LDL.

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Nutritional and biochemical aspects of the hypolipidemic action of rice bran oil: A review

Rukmini C, Raghuram TC.

J Am Coll Nutr. 1991 Dec;10(6):593-601.

In this paper, we review the effects of rice bran oil (RBO), an unconventional oil recently introduced onto the Indian market for human use. RBO contains oleic acid (38.4%), linoleic acid (34.4%), and linolenic acid (2.2%) as unsaturated fatty acids, and palmitic (21.5%) and stearic (2.9%) acids as saturated fatty acids. The unsaponifiable fraction (4.2%) has total tocopherols (81.3 mg%), gamma-oryzanol (1.6%), and squalene (320 mg%). Oryzanol is a mixture of ferulic acid esters of triterpene alcohols such as cycloartenol (CA) (106 mg%) and 24-methylene cycloartanol (494 mg%). Studies on experimental rats demonstrated a hypolipidemic effect of RBO. The unsaponifiable fraction of RBO lowers cholesterol levels. Feeding phytosterols, CA, and 24-methylene cycloartanol in amounts present in RBO to hypercholesterolemic rats for 8 weeks indicates that CA alone reduces cholesterol and triglyceride levels significantly. Endogenous sterol excretion increases in animals given CA. The accumulation of CA in the liver inhibits cholesterol esterase activity, which in turn leads to reduction in circulating cholesterol levels. CA is structurally similar to cholesterol and may compete with the binding sites of cholesterol and sequestrate cholesterol, which is metabolized to its derivatives. RBO, which is rich in tocopherols and tocotrienols, may improve oxidative stability. Tocotrienols inhibit HMG CoA reductase, resulting in hypocholesterolemia. The hypolipidemic effect of RBO has also been established in human subjects. Thus, RBO could be a suitable edible oil for patients with hyperlipidemia.

Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee)

Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G, Ong A, Peterson DM, et al.

Am J Clin Nutr. 1991 Apr;53(4 Suppl):1021S-1026S.


A double-blind, crossover, 8-wk study was conducted to compare effects of the tocotrienol-enriched fraction of palm oil (200 mg palmvitee capsules/day) with those of 300 mg corn oil/d on serum lipids of hypercholesterolemic human subjects (serum cholesterol 6.21-8.02 mmol/L). Concentrations of serum total cholesterol (-15%), LDL cholesterol (-8%), Apo B (-10%), thromboxane (-25%), platelet factor 4 (-16%), and glucose (-12%) decreased significantly only in the 15 subjects given palmvitee during the initial 4 wk. The crossover confirmed these actions of palmvitee. There was a carry over effect of palmvitee. Serum cholesterol concentrations of seven hypercholesterolemic subjects (greater than 7.84 mmol/L) decreased 31% during a 4-wk period in which they were given 200 mg gamma-tocotrienol/d. This indicates that gamma-tocotrienol may be the most potent cholesterol inhibitor in palmvitee capsules. The results of this pilot study are very encouraging.

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Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias

Qureshi AA, Qureshi N, Hasler-Rapacz JO, Weber FE, Chaudhary V, Crenshaw TD, Gapor A, Ong AS, Chong YH, Peterson D, et al.

Am J Clin Nutr. 1991 Apr;53(4 Suppl):1042S-1046S.

Normolipemic and genetically hypercholesterolemic pigs of defined lipoprotein genotype were fed a standard diet supplemented with 50 micrograms/gtocotrienol-rich fraction (TRF) isolated from palm oil. Hypercholesterolemic pigs fed the TRF supplement showed a 44% decrease in total serum cholesterol, a 60% decrease in low-density-lipoprotein (LDL)-cholesterol, and significant decreases in levels of apolipoprotein B (26%), thromboxane-B2 (41%), and platelet factor 4 (PF4; 29%). The declines in thromboxane B2 and PF4 suggest that TRF has a marked protective effect on the endothelium and platelet aggregation. The effect of the lipid-lowering diet persisted only in the hypercholesterolemic swine after 8 wk feeding of the control diet. These results support observations from previous studies on lowering plasma cholesterol in animals by tocotrienols, which are naturally occurring compounds in grain and palm oils and may have some effect on lowering plasma cholesterol in humans.

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Effect of tocotrienols on hepatocarcinogenesis induced by 2-acetylaminofluorene in rats

Ngah WZ, Jarien Z, San MM, Marzuki A, Top GM, Shamaan NA, Kadir KA.

Am J Clin Nutr. 1991 Apr;53(4 Suppl):1076S-1081S.

The effects of tocotrienols on hepatocarcinogenesis in rats fed with 2-acetylaminofluorene (AAF) were followed morphologically and histologically for a period of 20 wk. No differences between treated and control rats in the morphology and histology of their livers was observed. Cell damage was extensive in the livers of AAF-treated rats but less extensive in the AAF-tocotrienols-treated rats when compared with normal and tocotrienols-treated rats. 2-Acetylaminofluorene significantly increases the activities of both plasma and liver microsomal gamma-glutamyltranspeptidase (GGT) and liver microsomal UDP-glucuronyltransferase (UDP-GT). Tocotrienols administered together with AAF significantly decrease the activities of plasma GGT after 12 and 20 wk (P less than 0.01, P less than 0.002, respectively) and liver microsomal UDP-GT after 20 wk (P less than 0.02) when compared with the controls and with rats treated only with tocotrienols. Liver microsomal GGT also showed a similar pattern to liver microsomal UDP-GT but the decrease was not significant. These results suggest that tocotrienols administered to AAF-treated rats reduce the severity of hepatocarcinogenesis.

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A comparison of tocopherol and tocotrienol for the chemoprevention of chemically induced rat mammary tumors

Gould MN, Haag JD, Kennan WS, Tanner MA, Elson CE.

Am J Clin Nutr. 1991 Apr;53(4 Suppl):1068S-1070S.

Two forms of vitamin E, tocopherol and tocotrienol, were tested for chemopreventive activity in two chemically induced rat mammary-tumor models. When mammary tumors were induced by 7,12-dimethylbenz(a)anthracene (DMBA, 50 mg/kg), only the tocotrienol group had a statistically significant increase in tumor latency. There was no effect of either compound on tumor multiplicity. When tumors were induced by N-nitrosomethylurea (NMU, 30 mg/kg), neither analogue of vitamin E modified latency, whereas tocotrienol increased tumor multiplicity. In summary, neither vitamin analog had a major impact on mammary-tumor development after tumor induction with either DMBA or NMU.

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