Tocotrienols, the vitamin e of the 21st century: its potential against cancer and other chronic diseases
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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.
ß 2010 Elsevier Inc. All rights reserved.
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
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).
human milk .
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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-
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.
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.
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
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
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
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
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.
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
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
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 .
to meet expectations. These trials showed that there was astatistically nonsigniﬁcant increased risks of prostate cancer in
8. Tocotrienol isoforms
vitamin E (a-tocopherol acetate) group. Similar negative resultswere previously reported with vitamin E when its effect was
The isoforms of tocotrienols, which differ in their number of
examined on cancer cardiovascular events . Are tocotrienols,
methyl groups, also differ in their biological activities (
the vitamin E that we should be investigating in the 21st century?
B.B. Aggarwal et al. / Biochemical Pharmacology 80 (2010) 1613–1631
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February 29, 2016 WSPC Proceedings - 9.75in x 6.5in Recent results and perspectives on cosmology and fundamental physics from microwave surveys∗ Carlo Burigana,1,2,3,a Elia Stefano Battistelli,4,b Micol Benetti,5,c Giovanni Cabass,4,d Paolo De Bernardis,4,e Sperello Di Serego Alighieri,6,f Eleonora Di Valentino,7,g Martina Gerbino,8,9,4,h Elena Giusarma,4,i Alessandro Gruppuso,1,3,j
Detail-Document #241001 −This Detail-Document accompanies the related article published in− PHARMACIST'S LETTER / PRESCRIBER'S LETTER October 2008 Volume 24 Number 241001 Stability of Refrigerated and Frozen Drugs —Chart modified November 2008— (Based on U.S. product labeling and relevant studies)