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Tocotrienols, the vitamin e of the 21st century: its potential against cancer and other chronic diseases



Contents lists available at Biochemical Pharmacology Tocotrienols, the vitamin E of the 21st century: Its potential against cancer andother chronic diseases Bharat B. Aggarwal Chitra Sundaram, Seema Prasad, Ramaswamy Kannappan Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston,TX 77030, USA Initially discovered in 1938 as a ‘‘fertility factor,'' vitamin E now refers to eight different isoforms that Received 9 June 2010 belong to two categories, four saturated analogues (a, b, g, and d) called tocopherols and four Accepted 27 July 2010 unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigatedextensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-kB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation.
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are saturated forms of vitamin E, whereas the tocotrienols areunsaturated and possess an isoprenoid side chain. Some evidence Preventing beriberi by eating unpolished rice, curing scurvy by suggests that human tissues can convert tocotrienols to tocopherols eating citrus fruits, and supporting fertility by eating leafy . Tocopherols consist of a chromanol ring and a 15-carbon tail.
vegetables—all of these life-sustaining properties of foods are The presence of three trans double bonds in the tail distinguishes related to factors that in 1912 came to be called vitamins (vita tocopherols from tocotrienols. The isomeric forms of tocotrienol are means life). In 1922, Herbert Evans and Katherine Bishop, two distinguished by the number and location of methyl groups on the prominent researchers from Berkeley, first isolated fat-soluble chromanol rings: a-tocotrienol is 5,7,8-trimethyl; b-tocotrienol is vitamin E from green leafy vegetables and described it as a fertility 5,8-dimethyl; g-tocotrienol is 7,8-dimethyl and d-tocotrienol is factor. Vitamin E was named tocopherol in 1924 and synthesized in 8-monomethyl. While leaves and seeds of most plants contain 1938 [for references, see Deficiency of this vitamin is now tocopherols, tocotrienols are present in only a very small fraction of known to cause severe degenerative diseases such as ataxia, plants and b). Although some activities of tocopherols and Duchenne muscular dystrophy-like muscle degeneration, and tocotrienols are compared in this review, tocotrienols are the infertility. Vitamin E is present in most edible oils to various primary focus.
extents, including those extracted from wheat germ oil, wheat, rice The name tocotrienol to denote a tocopherol with a true bran (0.035%), barley (0.012% or 44 mg/g oil), oats (0.03%), coconut isoprenoid side chain was first suggested by Bunyan et al. , and (0.019%) and palm (0.044%; 0.78–1.08 mg/g oil) ( the tocotrienols were described in Nature when isolated from the latex of the rubber plant, Havea brasiliensis, in 1964 The While alpha-tocopherol was the first vitamin E analogue to be tocotrienols attracted no real attention until the 1980s and 1990s recognized, eight chemically distinct analogues are now known, when their cholesterol-lowering potential and anticancer consisting of alpha (a), beta (b), gamma (g) and delta (d)- effects were described Subsequently, rice bran, palm, and tocopherols (TP) and alpha, beta, gamma and delta-tocotrienols annatto (90% delta and 10% gamma) oils were described as some of (T3); all of them are referred to as vitamin E ). The tocopherols the richest sources of tocotrienols by Tan and his coworkers. Thetocopherols:tocotrienols ratios in rice bran, palm and annatto oilsare 50:50; 25:75 and 0.1:99.9, respectively . Besides tocopher-ols, various isomers of tocotrienols have also been detected in * Corresponding author. Tel.: +1 713 794 1817.
E-mail address: (B.B. Aggarwal).
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B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 growth-suppressive effects of this agent. Moreover, inhibition ofmitogen-activated protein kinases (MAPK) such as ERK p38MAPK and JNK is critical to the antiproliferative effects oftocotrienols. The suppression of cyclin D1 expression induced bytocotrienols also plays an important role in the growth-inhibitoryactivities of this vitamin Tocotrienols impedethe survival of various tumor cells by inhibiting expression of cellsurvival proteins such as XIAP, IAP-1, IAP-2, bcl-2, bcl-xl, c-FLIP,TRAF-1, survivin and Bfl-1/A1 . Suppression of the phospho-tidyl-inositol-3-kinase (PI3K)/AKT pathway by tocotrienols couldaccount for its antisurvival activities Downregulation of thetelomerase, c-myc, and raf–ERK signaling pathways has beenlinked to tocotrienol's ability to inhibit cell survival .
Various studies have revealed that tocotrienols can induce apoptosis in a wide variety of tumor cells. These effects aremediated through activation of both extrinsic and intrinsicpathways by the vitamin. The extrinsic pathways involveinduction of death receptors and activation of caspase-8,which leads to caspase-3 activation The activation of intrinsicpathways by tocotrienols involves mitochondrial depolarizationand is mediated through the upregulation of Bax cleavage of Bid release of cytochrome C , andactivation of caspase-9, which in turn leads to activation ofcaspase-3 . This unsaturated form of vitamin E alsomediates apoptosis through DNA fragmentation andupregulation of p53 in certain cells.
The suppression of angiogenesis by tocotrienols is mediated through inhibition of VEGF expression and VEGF receptorsignaling Suppression of the matrix metalloproteinase(MMP)-9 gene could also contribute to the angiogenesis-suppres-sive activity . Although TWIST, CXCR4, TNF, FGF, TGF-b,PDGF and IL-8 all have been linked with angiogenesis, whether anyof these pathways is modulated by tocotrienols is poorlyunderstood.
Numerous lines of evidence suggest that tocotrienols exhibit Fig. 1. Chemical structure of tocotrienols and tocopherols.
potent anti-inflammatory activity. First, activation of the tran-scription factor NF-kB has been closely linked with inflammationSecond, tocotrienols have been shown to suppress the 2. Molecular targets expression of TNF IL-1 IL-6 , IL-8 induciblenitric oxide synthase and cyclo-oxygenase 2 , all Like tocopherols, tocotrienols exhibit antioxidant activities, and of which mediate inflammation. Third, tocotrienols have been most of its effects can be linked to its antioxidant function.
shown to suppress STAT3 cell-signaling pathway, also involved in Molecular targets of tocotrienols can be classified as those that are inflammation Hypoxia-induced factor-1 is another path- modulated by binding directly and those that are way that has been linked with inflammation and is modulated by modulated indirectly. Modulation of various targets by tocotrie- tocotrienols .
nols may occur at the transcriptional, translational, or post- Tocotrienols inhibit various protein kinases, including protein translational levels, or by direct interactions with cellular targets kinase C p60 Src , IkBa kinase and GSK-3b For instance, src and 3-hydroxy-3-methyl-glutaryl Inhibition of HMG-CoA reductase, an enzyme that is rate limiting coenzyme A (HMG-CoA) reductase are modulated through direct in the pathway to cholesterol biosynthesis also plays an binding, whereas inflammatory transcription factors and the genes essential role in the various activities attributed to this vitamin.
regulated by them and death receptors are modulated indirectly There are, for instance, reports that the antitumor effects of and b). Various studies indicate that tocotrienols exhibit tocotrienols are linked to its ability to inhibit HMG-CoA reductase antioxidant, antiproliferative, antisurvival, proapoptotic, antian- Different isomeric forms of tocotrienols vary in their giogenic, and anti-inflammatory activities.
ability to lower cholesterol, as follows: d > g > a > b . The The antioxidant activities of this vitamin E (tocotrienols) are reduction of HMG-CoA occurs through two separate mechanisms, mediated through induction of antioxidant enzymes such as first the enhancement of degradation of the reductase protein and superoxide dismutase , NADPH:quinone oxidoreductase second the decrease in efficiency of translation of the reductase and glutathione peroxidase , which quench free radicals such as superoxide radicals (). The antiproliferative The modification by tocotrienols of various cell-signaling activity of tocotrienols are mediated through modulation of pathways described here has been linked to its effects against growth factors such as vascular endothelial growth factor (VEGF) cancer, diabetes, and cardiovascular and neurological diseases.
, basic fibroblast growth factor (bFGF) and transforminggrowth factor-beta (TGF-b) HER2/neu and interleukin-6 3. In vitro studies (IL-6) Cyclin-dependent kinases (CDK2, CDK4, CDK6) andtheir inhibitors, such as p21, p27 and p53 and down- Numerous in vitro studies indicate that tocotrienols exhibit regulation of Rb phosphorylation also mediate the anticancer, cardioprotective, and neuroprotective effects ).
B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Table 1A list of molecular targets modulated by tocotrienols in various cell types.
Apoptotic regulators Transcription factors Adhesion molecules Modulation of various targets by tocotrienol at transcription, translation, post-translation or by direct interaction are indicated by the superscripts 1, 2, 3 or 4, respectively.
12-LOX, 12-lipoxygenase; Apo A, apolipoprotein A; bFGF, basic fibroblast growth factor; CDK, cyclin-dependent kinases; C/EBPa; CCAAT/enhancer-binding protein-alpha;CHOP, C/EBP homologous protein; COX-2, cyclo-oxygenase-2; Cyt C, cytochrome C; DR5, death receptor 5; EGFR, endothelial growth factor receptor; eNOS, endothelial nitricoxide synthase; ER-a, estrogen receptor alpha; ERK, extracellular signal-regulated kinase; FLIP, FLICE-like inhibitory protein; GGT, gamma-glutamyl transpeptidase; GPx,glutathione peroxidase; GSH, reduced glutathione; GST, glutathione S-transferase; HIF-1a, hypoxia-inducible factor-1alpha; HMGCR, 3-hydroxy-3-methyl-glutarylcoenzyme A reductase; hTERT, human telomerase reverse transcriptase; IAP, inhibitors of apoptosis; ICAM-1, intercellular adhesion molecule-1; Id-1, inhibitor ofdifferentiation; IFN, interferon; IKK, IkB kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun NH(2)-terminal kinase; LDL-R, low-density lipoproteinreceptor; MAO-A, monoamine oxidase A; MAPK, mitogen-activated pathway kinase; MMP, matrix metalloproteinase; NF-kB, nuclear factor-kappa B, NQO1,NAD(P)H:quinone oxidoreductase; PARP, poly (ADP-ribose) polymerase; PDK, phosphoinositide-dependent protein kinase; PDK-1, Pl3K-dependent kinase 1; Pl3K,phosphoinositide 3-kinases; PF-4, platelet factor-4; PGE, prostaglandin; p-GSK3b, phospho-glycogen synthase kinase3 beta; PKC, protein kinase C; PLA(2), phospholipaseA(2); PPAR, peroxisome proliferator-activated receptors; PXR, pregnane X receptor; SOD, super oxide dismutase; SREBP, sterol regulatory element binding proteins; STAT,signal transducer and activator protein; SXR, steroid and xenobiotic receptor; TGF-b RII, tissue growth factor-beta receptor II; TIMP, tissue inhibitor of metalloproteinases;TNF, tumor necrosis factor; TRAF, TNF receptor-associated factor 1; TX-B2, thromboxane B2; VCAM-1, vascular cell adhesion molecule; VEGFR, vascular endothelial growthfactor receptor; XIAP, X-linked inhibitor of apoptosis protein.
3.1. Anticancer effects enzyme in cholesterol biosynthesis and reduce theexpression of adhesion molecules and monocyte–endothelial cell Tocotrienols have been shown to suppress proliferation and induce apoptosis in wide variety of tumor cells including those of thebreast 3.3. Neuroprotective effects , liver , lung , stomach skin, pancreas , and prostate A number of Various reports suggest that tocotrienols are neuroprotective, mechanisms have been proposed by which tocotrienols induce as indicated by its ability to suppress glutamate-induced activation apoptosis in these cancer cells, as already described. Some additional of c-Src kinase Tocotrienols also have activity against mechanisms involve induction of death receptor-5, as described Parkinson disease .
recently . Interaction of tocotrienols with estrogen receptors hasbeen implicated in studies of breast cancer cells Various 4. Animal studies with tocotrienols results indicate that g- and d-tocotrienol exhibit greater anticanceractivity than a- or b-tocotrienol .
4.1. Anticancer effects 3.2. Cardioprotective effects Tocotrienols exhibit activity in different models of both prevention and treatment of cancer ). Perhaps the first Tocotrienols' cardioprotective effects are mediated through report about the therapeutic potential of tocotrienols for cancer in their antioxidant mechanisms and their ability to suppress animal models was by Kato et al., who in 1985 showed that inflammation, and inhibit HMG-CoA reductase, a rate-limiting tumor-bearing rats administered with tocotrienols had an


B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Fig. 2. (a) Natural sources of tocotrienols. For reference see red annatto ; palm oil rice bran oil grape seed oil, maize, wheat germ oil hazel nut ;olive oil ; buckthorn berry ; rye ; oat and barley flax seed oil, poppy seed oil, safflower oil . (b) Content of tocotrienol and tocopherol isomers fromvarious sources. For reference see extended life span . Komiyama et al. observed antitumor a-tocotrienol as an antitumor agent They also showed activity when tocotrienols were administered intraperitoneally to that tocotrienols are better antioxidants than tocopherols. The mice with established murine Meth A fibrosarcoma. They showed growth of highly metastatic B16 melanoma in female mice was that tocotrienols were more effective than a-tocopherol, and inhibited by tocotrienols, and d-tocotrienol was more active than among the tocotrienols, g-tocotrienol was more effective than g-tocotrienol in this setting . In mice implanted with


B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Fig. 3. (a) Molecular targets of tocotrienols. (b) Proteins that directly interact with tocotrienols.
hepatoma, both g-tocotrienol and d-tocotrienol delayed tumor lymphoblastoid cells. They showed that g- and d-tocotrienol growth, and when examined for levels of tocotrienols, the tumors derived from palm oil exhibit strong activity against tumor contained a specific accumulation of these analogues .
promotion by inhibiting EBV early antigen expression in Raji cells The antitumor effects of tocotrienols appear to be mediated in induced by phorbol ester. However, a- and g-tocopherol and part through their ability to suppress angiogenesis .
dimers of g-tocotrienol or g-tocopherol lack this activity . Iqbal Suppression of angiogenesis is mediated through reduction in et al. showed that feeding tocotrienol-rich fraction (TRF; 10 mg/ serum levels of VEGF and inhibition of the PI3K–AKT pathway. The kg) to DMBA-administered rats suppressed mammary carcino- inhibition of HMG-CoA reductase and the consequent decrease in genesis, and this correlated with declines in serum cholesterol, serum cholesterol level has been linked with the tumor-suppres- low-density lipoprotein (LDL)-cholesterol, and HMG-CoA reduc- sive action of tocotrienols . Tocotrienols have also been shown tase protein Wada et al. examined the effect of 0.05% oral to enhance the antitumor effects of other agents. In one study, d- tocotrienols on spontaneous liver carcinogenesis in male mice and tocotrienol was reported to enhance the growth-suppressive on glycerol-induced lung tumor promotion in male mice initiated effects of lovastatin in the B16 melanoma model in mice .
with 4-nitroquinolone 1-oxide . Incidence of liver and lung g-Tocotrienol preferentially sensitized human prostate cancer in tumors was almost 80% lower in treated animals than in untreated nude mice to radiation .
Besides antitumor effects against established tumors, toco- Tocotrienols have been shown to prevent chemical-induced trienols have also been shown to be effective in cancer prevention carcinogenesis of the liver and found to suppress 2- models. Sundram et al. showed that palm oil, one of the richest acetylaminofluorene (AAF)-induced hepatocarcinogenesis dietary sources of tocotrienols, is effective in preventing 7,12- In another study, Rahmat et al. examined the effect of dimethylbenz[a]anthracene (DMBA)-induced mammary carcino- long-term administration of tocotrienols on hepatocarcinogenesis genesis in rats, but corn oil and soybean oil, which contain in rats. Liver carcinogenesis was induced by diethylnitrosamine and tocopherols but not tocotrienols, lack this activity . Gould et al.
AAF in rats fed a diet containing 30 mg/kg tocotrienols for 9 months.
reported a statistically significant increase in tumor latency in the Expression of biomarkers of liver carcinogenesis such as glutathione, DMBA-induced rat mammary tumor model with tocotrienols but alkaline phosphatase, and gamma-glutamyl transpeptidase was not with tocopherols Inhibition of tumor promotion by enhanced by the carcinogens but attenuated by tocotrienols, various palm-oil tocotrienols was also reported by Goh et al. decreasing the impact of the carcinogens. A similar study by others in an in vitro assay utilizing the activation of Epstein–Barr virus confirmed these findings . All these studies suggest that (EBV) early antigen expression in EBV-genome-carrying human tocotrienols have potential to both prevent and treat cancer.
B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Table 2In vitro studies with tocotrienols for effects against cancer, cardiovascular and neurodegenerative diseases.
Anticancer effect Inhibited estrogen receptor-negative and -positive cell proliferation Inhibited growth of cells irrespective of estrogen receptor status Induced cell death by DNA fragmentation Suppressed preneoplastic mammary epithelial cell proliferation Induced apoptosis through caspase pathway Induced apoptosis through mitochondria-mediated death pathway Induced apoptosis through TGF-beta–Fas–JNK-signaling pathways Inhibited cell proliferation and induced apoptosis in neoplastic mammary cells Exhibited synergism with statin in suppressing proliferation of tumor cells Exhibited synergism with phytochemicals in suppressing proliferation of tumor cells Exhibited synergism with celecoxib in suppressing proliferation of tumor cells Exhibited synergism with erlotinib/gefitinib in suppressing tumor cell proliferation Inhibited proliferation by arresting cell-cycle progression Inhibited tumor cell growth by suppressing HMGR activity Induced apoptosis in tumor cells through endoplasmic reticulum stress Inhibited proliferation through downregulation of Id1 protein Reduced cell viability and induced apoptosis via the mitochondrial pathway Inhibited colony formation through death receptor-5 and CHOP upregulation Inhibited growth and colony formation through DNA fragmentation Induced apoptosis and inhibited cell proliferation through cell-cycle arrest Showed synergistic inhibition of cancer cell growth Reduced cell viability and proliferation through DNA fragmentation Exerted antiproliferative effect by inducing S phase arrest Induced Bax and Bid regulated apoptosis Induced apoptosis on accumulation of cells in G1 phase through mutation of ras genes Suppressed survival and invasion capacity of the tumor cells Enhanced cisplatin-induced cytotoxicity in mesothelioma cells Induced apoptosis through downregulation of the Raf–ERK signaling pathway Inhibited cell migration and invasion through downregulation of matrix metalloproteinase Induced apoptosis via mitochondria-dependent apoptosis pathway Inhibited cell proliferation and potentiated lovastatin-mediated growth suppression Induced apoptosis by activating procaspases and accumulating sub-G1 cell population Induced apoptosis and cycle arrest at G1 phase Inhibited cell growth Inhibited cellular proliferation and accelerated apoptotic events Suppressed cell proliferation and invasion through multiple-signaling pathways Activated caspase-dependent programmed cell death Inhibited growth of human and mouse tumor cells Inhibited tumor promotion in human lymphoblastoid cells Inhibited both proliferation and tube formation and minimized tumor angiogenesis Inhibited angiogenesis and telomerase activity Inhibited pol lambda activity and angiogenesis Cardiovascular diseases Inhibited surface cell expression and adhesion Inhibited cholesterol biosynthesis Inhibited glutamate-induced death of HT4 neuronal cells Inhibited H2O2-induced neuronal death and oxidative stress-mediated cell death Attenuated homocysteic acid-induced neurotoxicity Prevents oxidative stress stimulated cell death of cortical neurons cells Protected methylmercury-induced neuronal cell death CHOP, C/EBP homologous protein; ERK, extracellular signal-regulated kinase; HMGR, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; Id1, inhibitor of differentiation;JNK, c-Jun N-terminal kinase; TGF, transforming growth factor.
4.2. Cardioprotective effects that the tocotrienols' effects were more pronounced than those ofa-tocopherol TRF from palm oil can reduce total cholesterol Persistent hypertension is one of the risk factors for strokes, and LDL-cholesterol levels through downmodulation of hepatic heart attacks, and heart failure and is a leading cause of chronic HMG-CoA reductase activity . Whether rice bran oil with its renal failure. Most of the cardioprotective effects of tocotrienols high content of g-oryzanol and g-tocotrienol has the same effect are mediated through their ability to inhibit a rate-limiting has been investigated in rats . A rice bran oil diet lowered enzyme in cholesterol biosynthesis and their antioxidant and anti- plasma triglyceride, LDL-cholesterol and hepatic triglyceride inflammatory activities. In one study, tocotrienols significantly concentrations and increased hepatic cholesterol 7-alpha-hydrox- depressed age-related increases in systolic blood pressure of ylase, hepatic LDL receptor, and HMG-CoA reductase mRNA in rats.
spontaneously hypertensive rats, and the investigators concluded The g-oryzanol and g-tocotrienol in rice bran oil can lead to B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Table 3A list of animal studies with tocotrienols for pharmacokinetics and for effects against cancer, cardiovascular, diabetes, neurodegenerative diseases, bone metabolism andother diseases.
Increased LLU-alpha concentration by oral administration in rats Selective uptake of T3 into the rat skin Distribution and bioavailability of a-, g-T3 in rats elevated by sesame Distribution and metabolism in adipose tissues and skin of rats NOAEL of toxicity by T3 in rats Stimulated sodium excretion in vivo in rats Bioavailability (delivered by ip and im than oral) in rats Effective distribution of T3 homologues to rat eye tissues Preferential absorption of a-T3 than g- and d-T3 Postprandial levels of the natural vitamin E-T3 in human circulation Tissue distribution and accumulation in adipose tissue Fast intestinal uptake of g-T3 More extensive metabolism of g-T3 than g-TP in rats Bioavailability of d-T3 is longer in pancreas with no toxicity Anticancer effects Inhibited mammary carcinogenesis in female rats Effective against sarcoma, Ehrlich and IMC carcinoma Reduced the severity of AAF-induced hepatocarcinogenesis in rats Attenuated DEN and AAF-induced hepatocarcinogenesis in rats Reduced AAF-induced increase in enzyme activities in rats Inhibited tumor promotion Suppressed the growth of B16 melanoma in mice Inhibited chemical-induced cancer in rats Suppressed DMBA-induced mammary tumors and hypercholesterolemia Inhibited TPA-induced skin carcinogenesis Delayed the onset, incidence and size of human breast cancer in nude mice Suppressed liver and lung carcinogenesis in mice Radio sensitized human prostate tumors in nude mice Potentiated lovastatin-induced growth suppression Reduced UVB-induced sunburn and incidence of tumor in hairless mice Delayed tumor growth in mice hepatoma Suppressed tumor growth via angiogenesis Chemosensitizer in hormone refractory prostate cancer Suppressed neovascularization in tumor cell-implanted mice Anti-angiogenic effect in BALB/c mice model, reduced VEGF Cardiovascular disorders Depressed the age-related increase in blood pressure of SHR Decreased levels of MDA and preserved continuity of IEL in rabbit aorta Reduction in atherosclerotic lesion size by d-P25-T3 in mice Increased nitric oxide activity and reduced the blood pressure in rats Activated NO–cGMP pathway and reduced ischemia/reperfusion myocardial injury in rats Reduced myocardial infarct size in rats Reduced autophagy during MI by elevating Beclin, LC3-II and mTOR signaling in rats Diabetes mellitus Prevented increase in AGE in streptozotocin-induced diabetic rats Protected against oxidative damage in diabetic KKAy mice Reduced the antioxidant biomarker level in mice Reduced serum creatinine level, creatinine clearance, U albumin and protein excretion in ODS rats Modulated streptozotocin-induced inflammation in diabetic rats Modulated diabetes-induced cognitive impairment Lowered the blood glucose level and improved dyslipidemia in diabetic rats Improved insulin sensitivity in mice through activation of PPARs Inhibited glutamate-induced pp60(c-Src) kinase activation and death of HT4 cells Expressed T3 sensitive genes in the developing rat fetal brain Modulated 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration Prevented cerebral infarction induced by MCA occlusion Protected against glutamate- and stroke-induced neurodegeneration Inhibited c-Src activity leading to prevention of glutamate-induced neurodegeneration Attenuated oxidative–nitrosative stress and inflammatory cascade in experimental model of diabetic neuropathy Prevented intracerebroventricular STZ-induced cognitive impairment and oxidative–nitrosative stress Ameliorated behavioral and biochemical alterations in the rat model of alcoholic neuropathy Prevented chronic alcohol-induced cognitive dysfunction by suppression of neuroinflammation Inhibited glutamate-induced activation of phospholipase A2 Reduced bone resorption to a greater extent than bone formation in thyrotoxic rats Helped in normal bone calcification in female Reduced body fat mass and increased bone calcium content in adrenalectomized rats Reversed nicotine-induced bone loss in rats Reversed free radical-induced bone loss in rats Exhibited antioxidant activity and prevented imbalance in bone metabolism due to free radicals in rats Acted as an anabolic agent for bone in normal male rats Improved normal bone structure B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Table 3 (Continued ) Inhibited cholesterol esterase activity in rats Reduced lipid peroxidation and enhanced superoxide dismutase activity in SHR Inhibited HMGCR, increased HDL, lowered LDL and TC in pigs Improved the lipid profile, lowered TG and increased HDL-c in rats Enhanced cholesterol catabolism by increasing LDL-R and HMG-CoA level in rat liver Increased fecal excretion of neutral sterol and bile acids in rats Suppressed Akt phosphorylation in 3T3-L1 preadipocytes in rats Enhanced proliferation and function of spleen and MLN lymphocytes Prevented aspirin-induced gastric lesion Blocked stress-induced changes in the gastric acidity and gastrin level in rats Maintained renal morphology against iron induced renal dysfunction AAF, 2-acetylaminofluorene; AGE, advanced glycosylation end-products; d-P25-T3, didesmethyl tocotrienol; DEN, diethyl nitrosamine; DMBA, 7,12-dimethylbenz[a]an-thracene; HDL, high-density lipoprotein; HDL-c, HDL cholesterol; HMG-CoA, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; HMGCR, HMG-CoA reductase; IEL, internalelastic lamina; LDL, low-density lipoprotein; LDL-R, LDL receptor; LLU-alpha, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxy chroman; LP, lipid profile; MCA, middlecerebral artery; MDA, malondialdehyde; MI, myocardial infarct; MLN, mesenteric lymph node; m-TOR, mammalian target of rapamycin; NF-kB, nuclear factor-kappa B;NOAEL, No-observed-adverse-effect level; NO–cGMP, nitric oxide–cyclic GMP; ODS, osteogenic disorder shionogi; PPAR, peroxisome proliferator-activated receptors; SHR,spontaneously hypertensive rats; STZ, streptozotocin; TC, total cholesterol; TG, triglyceride; TPA, 12-O-Tetradecanoyl-phorbol-13-acetate; VEGF, vascular endothelialgrowth factor.
increased neutral sterol and bile acid excretion in feces via superoxide dismutase activity . The investigators concluded upregulation of cholesterol synthesis and catabolism. Chou et al.
that antioxidant supplementation with g-tocotrienol may prevent observed that rice bran oil improved lipid abnormalities, reduced development of increased blood pressure, reduce lipid peroxides in the atherogenic index and suppressed the hyperinsulinemic plasma and blood vessels and enhance total antioxidant status, response in rats with streptozotocin/nicotinamide-induced type including superoxide dismutase activity.
2 diabetes mellitus Myocardial ischemic injury results from severe impairment of In atherosclerosis, build-up of fatty materials such as choles- coronary blood supply and produces a spectrum of clinical terol leads to artery wall thickening. Nafeeza et al. investigated the syndromes. Although all of the tocotrienol isomers have cardio- effect of TRF on the microscopic development of atherosclerosis protective properties against myocardial ischemic injury, g- and lipid peroxidation in the aortas of rabbits. After 10 weeks of tocotrienol was the most protective. The differential interaction treatment with TRF, cholesterol-fed rabbits had lower aortic of MAPK with caveolin 1/3 in conjunction with proteasome contents of malondialdehyde, less intimal thickening and greater stabilization plays a unique role in tocotrienols-mediated cardi- preservation of the internal elastic lamina than untreated rabbits oprotection, possibly by altering the availability of prosurvival and . Because TRF lowered lipid peroxidation, which in turn antisurvival proteins .
reduces intimal thickening and preserves the internal elastic In a study of the cardioprotective properties of g-tocotrienol in lamina, they concluded that the antioxidant activities of TRF could combination with resveratrol, the two agents acted synergistically, reduce experimental atherosclerosis.
providing a greater degree of cardioprotection than either alone TRF and isomers of tocotrienols can improve postischemic . The basis of this effect is their ability to induce autophagy ventricular function and reduce myocardial infarct size. They exert accompanied by activation of Beclin and LC3-II as well as mTOR this cardioprotective effect through downmodulation of c-Src and signaling while simultaneously generating a greater amount of upregulation of phosphorylation of Akt, thus generating a survival survival signal through activation of the Akt–Bcl-2 survival pathway.
signal A 6-week treatment of diet supplemented with eitherd-P(21)-T3, d-P(25)-T3, g-T3, or TRF showed significant effects on 4.3. Effects against diabetes mellitus lipid metabolism in swine expressing hereditary hypercholester-olemia Levels of serum total cholesterol, LDL-cholesterol, In diabetes the blood glucose level is persistently high because apolipoprotein B, platelet factor 4, thromboxane B(2), glucose, of insufficient insulin production or insulin resistance. TRF triglycerides, and glucagon were reduced in all of the treatment prevented increases in serum levels of advanced glycosylation groups relative to the control. The hepatic HMG-CoA reductase end-products (AGE) in normal rats and decreased blood glucose activity was lower, and cholesterol and fatty acid levels in various and glycated hemoglobin levels in diabetic rats . In a similar tissues were lower in all of the treatment groups.
study, TRF treatment not only reduced serum glucose and glycated Activation of the nitric oxide–cGMP pathway is associated with hemoglobin concentrations, it also reduced plasma total choles- myocardial protection against ischemia; in ischemia, the function terol, LDL-cholesterol and triglyceride levels and increased levels of this pathway is disturbed. Esterhuyse et al. investigated the of high-density lipoprotein (HDL)-cholesterol, as compared to the effects of red palm oil on the myocardial nitric oxide–cGMP untreated group Tocotrienols exert these effects through signaling pathway . Treatment with red palm oil increased increasing superoxide dismutase activity and levels of vitamin C in aortic output and increased levels of cGMP and polyunsaturated plasma and decreasing levels of plasma and aorta malondialde- fatty acid in rat hearts. Their findings suggest that dietary red palm hyde and 4-hydroxynonenal and oxidative DNA damage. Thus TRF oil protects via the nitric oxide–cGMP pathway and/or changes in lowers blood glucose level and oxidative stress markers, improves polyunsaturated fatty acid composition during ischemia/reperfu- dyslipidemia, and maintains vessel wall integrity. A combination sion. As red palm oil contains both tocopherols and tocotrienols, it of insulin and tocotrienol treatment attenuated the diabetic is unclear which of these constituents exerted the cardioprotective condition and reversed neuropathic pain through modulation of effect. Newaz et al. determined the effects of g-tocotrienol on lipid oxidative–nitrosative stress and release of inflammatory cytokines peroxidation and total antioxidant status of spontaneously and caspase-3 in diabetic rats . In another study, hypertensive rats. Their study showed that a 3-month antioxidant suppression of the NF-kB signaling pathway by tocotrienols trial with g-tocotrienol reduced blood and plasma concentrations prevented diabetes-associated cognitive deficits. Rats with strep- of lipid peroxides and improved total antioxidant status and tozotocin-induced diabetes were treated with oral tocotrienols B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 (25 mg/kg, 50 mg/kg or 100 mg/kg body weight) for 10 weeks, expression profiling. HO-3, LINE-1, and ApoB are some of the vitamin which significantly prevented behavioral, biochemical and molec- E-sensitive genes affected by vitamin E treatment ular changes associated with diabetes, in part through suppression A cerebral infarction is an ischemic kind of stroke caused by a of activation of the NF-kB signaling pathway .
disturbance in the blood vessels supplying blood to the brain. a- Oxidative stress is considered to be a key factor in the Tocopherol, a-tocotrienol and g-tocopherol significantly de- development of diabetes and its complications. Kanaya et creased the size of cerebral infarcts in the mice middle cerebral examined the antioxidative effects of a crude lipophilic rice bran artery occlusion model, while g-tocotrienol, d-tocopherol and d- extract, Ricetrienol, which contains a-tocopherol, tocotrienols, and tocotrienol showed no effect . Tiwari et al. demonstrated the phytosterol, in obese diabetic KKAy mice While Ricetrienol effectiveness of tocotrienols in attenuation of alcoholic neuropathy did not affect hyperglycemia, body weight, or hyperlipidemia, it . Treatment with a-tocopherol and tocotrienols (mixture of did significantly suppress elevation of plasma malondialdehyde a-, b-, g-tocotrienol) for 10 weeks significantly improved and significantly increase glutathione peroxidase (GPx) mRNA nociceptive threshold, paw-withdrawal threshold and superoxide expression at the 0.1% concentration; the authors suggested that dismutase levels and decreased tumor necrosis factor alpha (TNF- Ricetrienol exerts a protective effect against oxidative damage in a) and IL-1b levels in male Wistar rats. In another study, they diabetes mellitus. Yoshida et al. evaluated the antioxidant investigated the effect of a-tocopherol and a-tocotrienol against properties of natural and synthetic dietary antioxidants by using the biomarker, total hydroxyoctadecadienoic acid (tHODE) .
pairment and oxidative–nitrosative stress in rats. Both isoforms Remarkable increases in tHODE and total 8-iso-prostaglandin F effectively attenuated the reductions in glutathione and catalase (2alpha) (t8-iso-PGF (2alpha)) levels were observed in the plasma, and reduced the malondialdehyde, nitrite and cholinesterase erythrocytes, liver and brain of mice that were fed an a- activity in the brains of these rats, but the effect was more potent tocopherol-stripped (E-free) diet, whereas levels of these markers with tocotrienols .
were reduced in mice treated with the E-free diet supplementedwith a lipophilic antioxidant (0.04% by wt) containing a- 4.5. Effects on bone metabolism tocopherol, a-tocotrienol, and g-tocopherol.
al. investigated the mechanism through which Tobacco smoking has been identified as a risk factor in the tocotrienols reduce blood glucose levels in patients and in development of osteoporosis, vitamin E supplements reverse preclinical animal models . They proposed that tocotrienols nicotine-induced bone loss and stimulate bone formation function as peroxisome proliferator-activated receptor (PPAR) Another group has shown that tocotrienols can reverse nicotine- modulators. PPARs are ligand-regulated transcription factors that induced bone loss in rats (Bone histomorphometric play essential roles in energy metabolism. Synthetic PPARa and parameters of adult male rats treated with TRF or g-tocotrienol but PPARg ligands have been used recently in the treatment of not with g-tocopherol (60 mg/kg) following nicotine treatment hyperlipidemia and diabetes. Both a- and g-tocotrienol activated showed significantly higher trabecular thickness and less eroded PPARa, while d-tocotrienol alone activated PPARa, PPARg, and surface than the control group. Tocotrienols are slightly superior to PPARd in reporter-based assays. Tocotrienols enhanced the tocopherols in attenuating the effects of tobacco; g-tocotrienol interaction between the purified ligand-binding domain of PPARa especially may have therapeutic potential to repair bone damage and the receptor-interacting motif of coactivator PPARg coacti- caused by chronic smoking. This vitamin is an anabolic agent for vator-1alpha. They also found that TRF improved whole-body bone in normal male rats .
glucose utilization and insulin sensitivity of diabetic Db/Db mice Other studies have shown that tocotrienols can reverse by selectively regulating PPAR target genes . All of these glucocorticoid-induced or free radical-induced bone loss in results indicate that tocotrienols have antidiabetic potential.
adrenalectomized rats and improve normal bonestructure possibly through its antioxidant activity 4.4. Neuroprotective effects in bone Maniam et al. investigated the effects of vitamin Eon lipid peroxidation and antioxidant enzyme levels in rat bones Numerous reports indicate that tocotrienols exhibit neuropro- . They found that palm-oil tocotrienols at the dose of 100 mg/ tective effects under a wide variety of conditions kg body weight significantly reduced the level of thiobarbituric Chopra and her group noted neuroprotection by tocotrienols in acid-reactive substance in the femur while significantly increasing an experimental model of diabetic neuropathy in the rat glutathione peroxidase activity compared to the control group; model of alcoholic neuropathy in chronic alcohol-induced these effects were not observed in rats treated with g-tocopherol.
cognitive dysfunction in rats , in intracerebroventricular Tocotrienols also showed a protective effect against free radical streptozotocin-induced cognitive impairment and oxidative–nitro- damage in the rat femur bones. Long-term glucocorticoid sative stress in rats , in diabetic nephropathy and in treatment is associated with severe side effects, such as obesity diabetes-associated cognitive deficits , all through suppression and osteoporosis. Ima-Nirwana et al. showed that treatment with of proinflammatory pathways. Sen and his group have examined g-tocotrienol (60 mg/kg body weight/day) reduced body fat mass extensively the prevention of glutamate-induced neurodegenera- and increased fourth lumbar vertebra bone calcium content in rats, tion by tocotrienols . They found that while a-tocopherol was ineffective Therefore, palm-oil- modulation of c-Src, 12-lipoxygenase and PLA2 is involved in the derived g-tocotrienol has the potential to be utilized as a neuroprotective effects of tocotrienols. Khanna et al. showed that a prophylactic agent in prevention of the skeletal side effects of subattomole quantity of a-tocotrienol, but not g-tocopherol, long-term glucocorticoid and tobacco use.
protected neurons from glutamate challenge. Rats given a a-tocotrienol supplement showed more protection against stroke- 4.6. Immunomodulatory effects induced injury through downregulation of c-Src activation and 12-lipoxygenase phosphorylation at the stroke site . Roy et al.
al. demonstrated the immunoregulatory effects of reported that dietary tocotrienols are bioavailable to both mother dietary a-tocopherol and mixture of tocotrienols on humoral- and and fetal brains and that the enrichment is greater in fetal brain cell-mediated immunity . Their results showed that toco- tissue. They also identified a specific set of vitamin E-sensitive genes pherols or tocotrienols feeding enhanced expression of interfer- in the developing rat fetal brain using GeneChip microarray on-gamma, IgA, and IgG, but not IgE, and decreased the proportion B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 of CD4+ T cells. Interestingly, tocotrienols decreased the expres- ability of a-tocotrienol was approximately 28%, while the sion of TNF-a. These investigators concluded that oral adminis- bioavailability of g- and d-tocotrienol were around 9% tration of tocopherols and tocotrienols affects the proliferation Phase I cytochrome p450 3A4 enzyme and P-glycoprotein at the and function of spleen and mesenteric lymph node lymphocytes.
gastrointestinal epithelium are implicated in the oral absorption oftocotrienols. Preferential absorption of a-tocotrienol over g- 4.7. Gastroprotective effects tocotrienol and d-tocotrienol in rats is in agreement with otherreports in pigs and lymphatic cannulated rats . These al. compared the impacts of tocopherols and differences may be linked to the number of methyl groups in the tocotrienols on gastric acidity, gastric tissue content of parameters chromanol ring, as a-tocotrienol has three, g-tocotrienol has two, such as malondialdehyde and prostaglandin E2, and serum levels and d-tocotrienol has one methyl group, and thus they have of gastrin and glucagon-like peptide-1 in rats exposed to restraint stress. They found that tocotrienol-treated animals, both stressed In another study, following a single oral administration of d- and non-stressed, had comparable gastric acidity and gastrin levels tocotrienol (100 mg/kg), the peak plasma concentration was . Both tocopherols and tocotrienols had gastroprotective 57  5 mmol/l, the time required to reach peak plasma concentration effects against damage by free radicals generated in stress was 2 h, and the plasma half-life was 3.5 h. The tocotrienols were conditions, but only tocotrienols had the ability to block stress- cleared from plasma and liver within 24 h, but clearance from the induced changes in gastric acidity and gastrin level. Another group pancreas was delayed . d-Tocotrienol was 10-fold more showed that tocotrienols can prevent aspirin-induced gastric concentrated in the pancreas than in the tumor and no toxicity lesions through their ability to limit lipid peroxidation .
was shown by d-tocotrienol (100 mg/kg) in mice. Intestinal epithelialcells absorb g-tocotrienol faster than a-tocopherol. Tocotrienol 5. Pharmacokinetics of tocotrienol isomers accumulated rapidly in Caco2 cells treated with micelles ofvitamin E isomers consisting of bile salts, lysophospholipids, free fatty Numerous studies on the pharmacokinetics, organ and tissue acid, and 2-monoacylglycerols and was greater than the accumula- distribution and toxicity of tocopherols and tocotrienols have been tions of corresponding tocopherol isomers This finding shows carried out . Yap et al. determined the pharmacokinetics that the difference in saturation of the side chains of tocopherols and and bioavailability of a-, g-, and d-tocotrienol given via oral, tocotrienols, rather than the difference in their rings, was responsible intravenous, intramuscular and intraperitoneal routes in rats. They for the rapid epithelial transport into the Caco2 cell membranes. a- found that oral absorption of all forms of tocotrienols was Tocopherol, a-tocotrienol and g-tocotrienol can all be retained incomplete and that absorption of tocotrienols given via the abundantly by the skin of rats and mice, but only a-tocopherol is intramuscular or intraperitoneal routes was negligible; they retained by the liver, kidney, and plasma of these animals concluded that these routes of administration should be avoided Dietary sesame seeds can elevate absorption and concentrations of a- . They also found that a-tocotrienol had greater bioavailabil- and g-tocotrienol in skin and adipose tissue Kawakami et al.
ity than g-tocotrienol and d-tocotrienol. The absolute bioavail- investigated the distribution of tocotrienols in rats and reported that Table 4Effects of tocotrienols in human subjects.
Biological effect Plasma transport and tissue concentrations of T3 in humans a- and g-T3 are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine Pharmacokinetics and bioavailability of a-, g- and d-T3 varies under different food status Lipolysis and droplet size affects T3 absorption from self-emulsifying formulations Postprandial metabolic fate of T3-rich vitamin E differs significantly from that of a-TP Daily supplementation of TRF did not induce immunomodulatory changes in healthy human volunteers Neoplastic disorders T3 concentration of adipose tissue of human breast with cancer T3 levels in adipose tissue of benign are higher than that in malignant breast lumps in patients in Malaysia Higher prediagnostic serum levels is associated with lower risk of developing prostate cancer Cardiovascular and metabolic disorders T3 lowers serum cholesterol in hypercholesterolemic humans Palmvitee lowered both serum total cholesterol and LDL-cholesterol in humans T3 induced decrease in cholesterol in hypercholesterolemic subjects T3 attenuates collagen-induced platelet aggregation in patients with hyperlipidemia and carotid stenosis T3 modulate cardiovascular diseases risk parameters of hypercholesterolemic humans T3 had no effect on serum lipids, lipoproteins, or platelet function in men with mildly elevated serum lipid a-Tocotrienyl acetate supplement decreased LDL oxidation in hypercholesterolemic humans T3 exhibit synergistic effects with lovastatin on lipid parameters in hypercholesterolemic humans T3 mixture does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia TRF (100 mg/day) suppressed serum cholesterol by in hypercholesterolemic humans T3 is beneficial in prevention and treatment of type 2 diabetic patients with hyperlipidemia T3 elevated plasma T3 levels but had no effect on lipid profile in healthy humans T3 but not TP reduced fasting serum lipid levels in patients with mild hypercholesterolemia T3 with citrus flavonoids decreased serum cholesterol levels in hypercholesterolemic subjects T3 (self-emulsifying preparation) improved arterial compliance in 36 healthy male Anti-aging effect T3 (160 mg  8 months) reduced DNA damage in older healthy adults (64) T3 improves long-term clinical outlook and survival in patients with neurodegenerative familial dysautonomia Topical a-T3 supplementation inhibited lipid peroxidation after benzoyl peroxide treatment of human skin T3, tocotrienols; TP, tocopherols; TRF, tocotrienol-rich fraction; LDL, low-density lipoprotein.


B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Fig. 4. Physiological functions of tocotrienols.
g-tocotrienol was significantly distributed to the adipose tissue and When the tocotrienol analogues were given at the same dose, that the adipose tissue concentration increased from 1.1 nmol/g to plasma levels of a-tocotrienol were twice those of g-tocotrienol 10.2 nmol/g according to rice bran tocotrienols intake .
and 10 times higher than those of d-tocotrienol. Another study Nakamura et al. examined the 13-week oral toxicity of a showed that a- and g-tocotrienol are metabolized to carbox- tocotrienol preparation in rats and found that the no-observed- yethyl-hydroxychroman derivatives and excreted in human urine adverse-effect level of tocotrienols was 0.019% in the diet (i.e., . When human subjects (n = 6) consumed 125 mg of 120 mg/kg body weight/day for male and 130 mg/kg body - tocotrienyl acetate daily for the first week, 500 mg daily for the weight for female rats). A decrease in total cholesterol was second week, 125 mg daily for the third week and 500 mg daily for observed in males in line with the hypocholestrolemic activity of the fourth week, only 1–2% of a-tocotrienol and 4–6% of g- this vitamin .
tocotrienol metabolites was recovered in the urine. To overcomethe limited oral bioavailability of tocotrienols, self-emulsifying 6. Clinical studies with tocotrienols formulations have been tested in healthy human volunteers withfavorable results .
Numerous clinical studies have been performed to examine bioavailability and various therapeutic effects of tocotrienols in 6.2. Effects on cardiovascular system About 50% of persons consuming the typical Western diet will 6.1. Pharmacodynamics and pharmacokinetics die of coronary heart disease or stroke. Hypercholesterolemiaand inflammation of the coronary artery are the major risk In a double-blind placebo-controlled study, the bioavailability factors for development of coronary heart disease. While dietary of purified a-, g- or d-tocotrienol (250 mg/day for 8 weeks) in fat has been associated with coronary heart disease, a diet of hypercholesterolemic humans was examined. At the end of the predominantly plant foods, such as rice, oats and barley (all of study period, plasma levels of a-tocotrienol, g-tocotrienol and d- which contain tocotrienols), can retard this disease. While some tocotrienol were 0.8 mM, 0.54 mM and 0.09 mM, respectively studies indicate that tocotrienols have cardioprotective proper- The preferential absorption of a-tocotrienol in humans ties in humans others have failed to show the noted here is in agreement with that noted in rats Hayes et al. reported that tocotrienols were transported by chylomicrons In the first study ever performed on the effects of tocotrienols in and disappeared from the plasma during chylomicron clearance human subjects, 22 healthy volunteers took one capsule daily Another study investigated the pharmacokinetics and containing a palm-oil-vitamin E concentrate (palmvitee) that bioavailability of a single oral dose (300 mg) of a-tocotrienol, g- comprised approximately 18 mg tocopherols, 42 mg tocotrienols tocotrienol and d-tocotrienol in healthy volunteers (N = 8) under and 240 mg palm olein for 30 days The investigators fed and fasting conditions. Oral bioavailability of all tocotrienol observed decreases in total cholesterol ranging from 5% to 35.9% analogues was markedly increased when taken with food, with and in LDL-cholesterol from 0.9% to 37% . These cholesterol- peak plasma concentrations (1.52–5.87 mM) occurring between 3 lowering effects were attributed to tocotrienols, as tocopherols has and 5 h after ingestion. The biological half-lives of a-tocotrienol, g- been shown in human subjects to lack these effects Qureshi tocotrienol and d-tocotrienol were 2.3 h, 4.4 h, and 4.3 h, al. performed a double-blind, crossover 8-week study respectively. The half-life of a-tocopherol is about 20 h; thus comparing the effect of 200 mg palmvitee/day with that of the half-lives of the tocotrienols are 4.5- to 8.7-fold shorter .
300 mg corn oil (which lacks tocotrienols) on the serum lipid B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 levels of 25 hypercholesterolemic human subjects. The serum risk for cardiovascular disease, the presence of even a borderline- cholesterol levels of seven subjects decreased by 31% during the 4- high-risk LDL-cholesterol level signals the need for aggressive week period of treatment that included tocotrienols, and this effect LDL-lowering therapy. Thus Baliarsingh et al. investigated the persisted even 2 weeks after the capsules were discontinued .
therapeutic impacts of tocotrienols on serum and lipoprotein lipid Later, in another clinical trial, Qureshi et al. administered TRF from levels in patients with type 2 diabetes in a randomized, double- rice bran oil in a 12-week double-blind study in 21 hypercholes- blind, placebo-controlled design involving 19 subjects with type 2 terolemic subjects. A 12% decrease in total cholesterol and 16% diabetes and hyperlipidemia. After 60 days of TRF treatment, reduction in LDL-cholesterol were noted in subjects given TRF subjects showed average declines of 23%, 30%, and 42% in serum during the 4-week period in which the dose was 200 mg but not in total lipids, total cholesterol, and LDL-cholesterol, respectively.
the placebo group given 1.2 g corn oil. Furthermore, a 17% decrease Tocotrienols mediated a reduction of LDL-cholesterol level from an in lipoprotein-a was noted in the treated group, which is average of 179 mg/ml to 104 mg/ml. No hypoglycemic effect was remarkable as most cholesterol-lowering drugs do not affect observed in these patients because their glucose and glycated hemoglobin levels at baseline were close to normal values The antioxidant benefit of tocotrienols has been reported in a These findings suggest that daily intake of dietary TRF by group of patients with cerebrovascular diseases. Both tocopherols individuals with type 2 diabetes will be useful in the prevention and 240 mg mixed tocotrienols were used in this trial In and treatment of hyperlipidemia and atherogenesis.
another clinical trial, low doses of TRF for 25 weeks were found toexhibit synergistic effects with lovastatin on various lipid parameters in hypercholesterolemic humans Further studiesrevealed that the effect of TRF on serum cholesterol levels was dose Familial dysautonomia, a genetic neurodegenerative disorder dependent when administered at 25 mg/day, 50 mg/day, 100 mg/ affecting primarily individuals of Ashkenazi Jewish descent, is day, or 200 mg/day. The maximum decrease (25%) was seen at the caused by mutations in the IKBKAP gene, which encodes the 100 mg/day dose .
IkappaB kinase complex-associated protein (IKAP). The more In contrast to these studies, Mensink et common or major mutation causes aberrant splicing, resulting in a randomized, double-blind, placebo-controlled trial in 20 mildly truncated form of IKAP. Tissues from individuals homozygous for hypercholesterolemic men who received 140 mg tocotrienols and the major mutation contain both mutant and wild-type IKAP 20 mg a-tocopherol for 4 weeks, that this regimen had no effect on transcripts. The apparent leaky nature of this mutation prompted a serum lipid levels . Whether the negative results were due to search for agents capable of elevating the level of expression of the the presence of the tocopherols are not clear, but a-tocopherol has wild-type IKAP transcript. It has been shown that tocotrienols can been shown to neutralize the HMG-CoA reductase-inhibitory increase the transcription of IKAP mRNA in familial dysautonomia- activity of tocotrienols These results do agree, however, with derived cells, with corresponding increases in the correctly spliced those of Wahlqvist et al. In another double-blind, placebo- transcript and normal protein. Because ingestion of tocotrienols controlled study, the serum cholesterol-lowering efficacy of elevates IKAP and MAO-A in familial dysautonomia patients, Rubin purified a-, g- or d-tocotrienol (250 mg/day) for 8 weeks in et al. examined their impact on the frequency of hypertensive hypercholesterolemic humans was examined. Although at the end crises and cardiac function in individuals with this disorder. After of the study period, plasma levels of a-tocotrienol, g-tocotrienol 3–4 months of tocotrienol ingestion, approximately 80% of patients and d-tocotrienol were 0.98 mM, 0.54 mM and 0.09 mM, respec- reported a significant (50%) decrease in the number of crises. In a tively, no change in serum or LDL-cholesterol levels were observed smaller group of patients, a postexercise increase in heart rate and . Alpha-tocotrienol did decrease the oxidizing potential of a decrease in the QT interval were observed . On the basis of LDL. Mustad et al. also showed a lack of effect of supplementation these findings, the authors hypothesized that tocotrienol therapy of tocotrienols (200 mg/day) on hypercholesterolemia .
improves the long-term clinical outlook and survival of individuals Another study examined the effects of three doses of with familial dysautonomia.
tocotrienol-rich vitamin E (TRE) on plasma tocotrienol isomer The free radical theory of aging suggests that free radicals are concentrations, arterial compliance, plasma total antioxidant the leading cause of deteriorating physiologic function during status, aortic systolic blood pressure, and serum total cholesterol senescence. Free radicals attack cellular structures or molecules and LDL-cholesterol levels in healthy men. This randomized, such as DNA, resulting in various modifications to the DNA.
blinded endpoint, placebo-controlled clinical trial with a parallel Accumulation of unrepaired DNA contributes to a variety of design involved 36 male subjects who took either an oral placebo disorders associated with the aging process. Chin and his or TRE at doses of 80 mg, 160 mg, or 320 mg daily for 2 months.
coworkers performed a randomized, double-blinded, placebo- Baseline tocotrienol isomer concentrations were low and in some controlled study to evaluate the effect of Tri E tocotrienol on DNA subjects, not detectable. At the end of the study period, all TRE- damage. Sixty-four subjects aged 37–78 years completed the treated groups showed significant increases in a-, d- and g- study. A daily dose of 160 mg of Tri E tocotrienol was given for 6 tocotrienol concentrations from baseline relative to the placebo months. Blood samples were analyzed for DNA damage using the group. There was a linear dose and blood level relationship for all comet assay, frequency of sister chromatid exchange, and the isomers. There was no significant difference between groups, chromosome 4 aberrations. Results showed that this treatment however, in pulse wave velocity, arterial compliance, plasma total significantly reduced DNA damage as measured by comet assay antioxidant status, aortic systolic blood pressure, or serum levels of after 3 months and that DNA damage remained low at 6 months.
total cholesterol or LDL-cholesterol from baseline to end of The frequency of sister chromatid exchange was also reduced treatment. Groups receiving 160 mg or 320 mg of TRE showed after 6 months of supplementation, most markedly in the subjects significant reductions in their aortic systolic blood pressure, and older than 50 years, while urinary levels of 8-hydroxy-20- the group receiving 320 mg showed a significant 9.2% improve- deoxyguanosine (8-OHdG) were significantly reduced. A strong ment in total antioxidant status .
positive correlation was observed between sister chromatid The progression of atherosclerosis is more rapid in individuals exchange with age, whereas weak positive correlations were with type 2 diabetes than in the general population, and 80% of observed in DNA damage and 8-OHdG, which were reduced with those with type 2 diabetes will die of an atherosclerotic event.
supplementation . However, no translocation or stable Since in these patients hyperglycemia per se confers increased insertion was observed in chromosome 4. Thus Tri E tocotrienol B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Table 5Tocotrienols are more potent than tocopherols.
T3 is more potent than TP in reducing gamma-glutamyl transpeptidase and glutathione S-transferase T3 is more potent than TP in inducing apoptosis of tumor cells T3s are more potent than TP in inhibiting growth and inducing apoptosis of mouse mammary epithelial cells T3s preferentially accumulate than TP in mouse mammary epithelial cells T3s are more effective than TP in preventing glutamate-induced neuronal cell death T3s, but not TP, inhibited both the proliferation and tube formation of bovine aortic endothelial cells T3s are more readily transferred and incorporated into the membranes than TP T3 had greater peroxy radical scavenging activity than TP in liposomal membrane T3, not TP inhibited human endothelial cell proliferation and suppressed tumor-induced angiogenesis T3, not TP reduced VEGF-stimulated tube formation in HUVEC T3 protects astrocytes better than TP from H2O2-induced-cell loss and apoptosis T3 is more effective than TP in protecting against glutamate-induced cell death in HT4 neuron cell T3s are more potent than TP in protecting cerebellar granule cells against methyl mercury toxicity Accumulation and secretion rate of T3 isomers in Caco2 cells is faster than TP isomers; oral administration caused faster appearance and disappearance of T3 than TP T3 is more effective than TP in suppressing LPS-induced IL-6, PGE2 production from macrophages T3 were more effective in inhibiting the growth of sarcoma 180, Ehrlich carcinoma, and IMC carcinoma than TP T3 showed significant increase in DMBA-induced tumor latency than TP T3 showed 40–60 times higher antioxidant activity against induced lipid peroxidation and 6.5 times better protection of cytochrome P-450 against oxidative damage than TP Reduction of linoleic acid desaturation was more clear with T3 than with TP No T3 in plasma but platelet concentration of d-T3 doubled; TP was found in LDL and HDL in human; T3 deposited in adipose tissue while TP was detected in all tissue except adipose in hamster Lymphatic transport and recovery of T3 was twice higher than that of TP in thoracis duct-cannulated rats T3 feeding (0.2% in diet) gave higher CD4+/CD8+ ratio than TP in mesenteric lymph node lymphocytes T3 exerted stronger antioxidant activity than TP in vivo T3 (60 mg/kg body weight/day) was more effective than TP in reducing body fat mass and preventing steroid-induced osteoporosis Concentration of T3 increased markedly in eye tissue than TP T3 but not a-TP reduced the serum levels of IL-1 and IL-6 in rats T3 (60 mg/kg body weight) was better than TP in protecting bone resorption caused by free-radicals T3 has the ability to block the stress-induced changes in the gastric acidity and gastrin level than TP T3 are detected in postprandial (fasted) human plasma earlier than TP but at significantly lower level than TP T3 is a better antioxidant than TP in a deep fat frying system Total cholesterol and LDL-C levels declined in T3 group but not in those on TP T3 is superior than TP in suppressing nicotine-induced loss of calcium from bone T3 but not TP reduced the levels of lipid peroxidation and increased GPO activity in the femur of rats T3, but not TP can maintain the noradrenalin level and prevent gastric lesions in rats exposed to stress T3 is more extensively than TP metabolized to sulfated CEHC form T3 was superior than TP, in reversing nicotine-induced bone loss in rats T3 has better effects than TP on static and dynamic bone histomorphometric parameters T3 is better than TP as an anabolic agent for bone in normal male rats CEHC, 2-(beta-carboxyethyl)-6hydroxychromon; DMBA, 7,12-dimethylbenz(a)anthracene; GPO, glutathione peroxidase; HDL, high-density lipoprotein; HUVEC-humanumbilical vein endothelial cells; IL, interleukins; LDL, low-density lipoprotein; LPS, lipopolysaccharide; PGE2, prostaglandin-2; T3, tocotrienols; TP, tocopherols; VEGF-vascular endothelial growth factor.
supplementation may be beneficial by reducing free radical cells and in inducing apoptosis Almost millimolar doses of damage as indicated by reductions in DNA damage, sister tocopherols were required for antiproliferative effects The chromatid exchange frequency and urinary 8-OHdG level. Topical authors showed that these differences could be linked to application of a-tocotrienol has been shown to prevent benzyl preferential accumulation of tocotrienols as compared to toco- peroxide-induced lipid peroxidation of human skin pherols. These differences may also be due to a-tocopheroltransfer protein, which binds to a-tocopherol with higher affinity 7. Tocotrienols vs. tocopherols than to tocotrienols . When their respective effects onproliferation of bovine endothelial cells, a marker of angiogenesis, Tocotrienols differ from tocopherols in that the former contain were measured, only tocotrienols (not tocopherols) inhibited this three double bonds in their isoprenoid side chain while the latter proliferation . Another study showed that oral administration do not; this may account for the differences in their efficacy and of tocotrienols but not tocopherols blocked tumor-induced potency in vitro and in vivo ) . While over angiogenesis. These investigators showed that tocotrienols down- 30,000 papers have been published on tocopherols, fewer than 600 regulated VEGF receptor expression in HUVEC cells and blocked exist on tocotrienols, most published within the last 5 years.
VEGF signaling .
Tocopherols are present mainly in corn, wheat and soybeans, Suarna et al. reported that when rats or humans were treated whereas tocotrienols occur mainly in barley, oats, palm, and rice with tocotrienols and tocopherols, tocotrienols provided oxidative bran. Although tocopherols and tocotrienols are structurally very protection but tocopherols did not a-Tocopherol has been similar and both are metabolized through similar mechanisms reported to attenuate the inhibitory effects of tocotrienols on involving initial v-hydroxylation followed by five cycles of b- HMG-CoA activity . Tocotrienols have been shown to be oxidation tocotrienols have been found to exhibit superior converted to tocopherols in vivo High concentrations of g- antioxidant activity . McIntyre et tocotrienol but not a-tocopherol were cytotoxic to astrocytes. This tocotrienols were several-fold more effective than tocopherols in difference was attributed to the greater prooxidant activity of inhibiting the proliferation of mouse mammary tumor epithelial tocotrienols at high concentrations. At low concentrations, B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631 Table 6Comparative effects of various tocotrienol isomers.
g-T3 is 30 more active than a-T3 or d-T3 in inhibiting cholesterol biosynthesis in HepG2 cells g-T3 is more active than a-T3, and d-T3 in oxidation of lipids and protein in brain mitochondria a-T3 exhibits faster lymphatic transport and higher absorption in rats than gT3 and d-T3 g-T3 is more active than a-T3, and d-T3 in oxidation of lipids and protein in liver microsomes g-T3 and d-T3 but not a-T3 inhibit growth of both ER+ and ER breast cancer cells d-T3 are more potent than other T3s in promoting apoptosis of breast cancer cells a-T3 was more active than g-T3 or d-T3 in preventing LDL oxidation in hypercholesterolemic humans g-T3 is more active than a-T3 or d-T3 in lowering total cholesterol in high fat diet fed hamsters g-T3 was more active than a-T3 or d-T3 in inducing PXR-mediated gene expression a-T3 but not g-T3 or d-T3 can prevent cerebral infarction in mice a-T3 is more potent than other T3 as antioxidant and as a prooxidant a-T3, but not g-T3 or d-T3 exhibit neuroprotective action in rat striatal neuron cells d-T3 is more active than b > g > a-T3 in inhibiting proliferation and tube formation of bovine aortic endothelial cells d-T3 is more potent than other isomers in inhibiting VEGF-stimulated tube formation by HUVEC d-T3 is more active than a-T3, b-T3 or g-T3 in suppression of adhesion of monocytes to endothelial cells via VCAM-1 d-T3 is more active than other T3 in suppression of tumors in vitro and in vivo g-T3 is better than a-T3 as an anti-oxidant g-T3 was more cardioprotective than a-T3 or d-T3 but d-T3 was most active in stabilizing proteasomes d-T3 is more active than a-T3 or d-T3 in inhibiting DNA polyl and angiogenesis d-T3 is more active than g-T3 and a-T3 as an antioxidant in rat liver microsomal membranes and cells d-T3 is more active than d-T3 in stimulating ubiquitination and degradation of HMG-CoA reductase d-T3 was more active than other isomers in induces cell death in AR and AR+ prostate cancer cell lines g-T3 is more potent than a-T3 or d-T3 in inhibiting proliferation and inducing apoptosis of HeLa cells g-T3 is better than d-T3 in promoting bone formation in male rats AR, androgen receptor; ER, estrogen receptor; LDL, low-density lipoprotein; HUVEC, human umbilical vein endothelial cells; PXR, pregnane X receptor; T3, tocotrienols;VCAM-1, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.
however, tocotrienols were found to be antioxidant and to protect While various studies have indicated that a-tocotrienol is highly cells from hydrogen peroxide-induced killing This is neuroprotective , d- and g-tocotrienol have been shown to consistent with studies showing that tocotrienols are more exhibit the greatest anticancer effects. In vitro studies suggest that effective than tocopherols in protecting against glutamate-induced there may be as much as a 30-fold difference in the ability of a, g, cell death in HT4 neuron cell culture . Whether these and d isomers of tocotrienol to inhibit cholesterol biosynthesis differences were due to the differential rates of uptake of The antioxidant capacity of these three isomers is a- tocotrienols and tocopherols by the neuronal cells is controversial tocotrienol > g-tocotrienol > d-tocotrienol The antioxidant . Tocotrienols were many times as potent as tocopherols in activity of a-tocotrienol is similar to that of a-tocopherol protecting cerebellar granule cells against methyl mercury McIntyre et al. showed that various tocotrienols differ in their toxicity, an effect that was linked to the difference in the potency in inhibiting the proliferation of mouse mammary tumor antioxidant potency of the two forms of the vitamin . In epithelial cells and in inducing apoptosis They identified the vitro studies showed that tocotrienols have greater anti-inflam- relative potencies of these three isomers as d-tocotrienol > g- matory activity than tocopherols as measured by lipopolysaccha- tocotrienol > a-tocotrienol. These observations agree with that of ride-induced production of IL-6 and prostaglandin E2 .
Inkouchi et al., who showed that the relative potencies for the Mishima et al. showed that a-tocotrienol and g-tocotrienol were suppression of proliferation of bovine and human endothelial cells more effective than a-tocopherol in preventing cerebral infarction and tube formation were d-tocotrienol > b-tocotrienol > g-toco- trienol = a-tocotrienol All these reports point to Any number of mechanisms could account for the difference in differences in the mechanisms of action of the tocotrienol isomers.
potency of tocotrienols and tocopherols. First, because of structuraldifferences, tocotrienols may be more uniformly distributed in the lipid bilayer. Second, the chromanol ring of tocotrienols mayinteract more efficiently with the lipid bilayer than that of While a lot is known about tocopherols, very little is known tocopherols. Third, tocotrienols may have a higher recycling about tocotrienols. There is some evidence, however, that efficiency Fourth, cellular uptake of tocotrienols is 70 times tocotrienols may be superior in its biological properties, and that higher than that of tocopherols All of these factors may its anti-inflammatory and antioxidant activities could prevent contribute to tocotrienol's greater efficacy. It has also been shown cancer, diabetes, and cardiovascular and neurodegenerative that tocotrienol isomers are accumulated and secreted at greater ). Tocotrienols were discovered a half-century rates in Caco2 cells than tocopherol isomers. When administered ago, but most of their biology has been revealed only in the last orally to mice, tocotrienols appeared faster in the plasma but at decade. More clinical and preclinical studies are needed to fully lower levels than tocopherols realize their potential. Disappointment with tocopherols, as Alpha-tocotrienol mediates some of its effect by inhibiting indicated by two recent very large randomized controlled clinical HMG-CoA reductase activity , while a-tocopherol induces trials for prevention of prostate cancer , is growing as it fails HMG-CoA reductase activity .
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