Table 1.
TOCOTRIENOL: A NEW FACE OF VITAMIN E UNFLODING
| Neuroprotective | 2000 | Mouse; At nM concentrations α-tocotrienol, in contrast with α-tocopherol, protects against glutamate-induced neuronal death by suppressing inducible pp60 c-src kinase activation. α-Tocotrienol provided the most potent neuroprotection among all vitamin E analogs. Reported effects of tocotrienol independent of antioxidant property (Sen et al., 2000) |
| 2002 | Rat; Oral tocotrienol crosses the blood-brain barrier to reach brain tissue; more so for fetal brain while pregnant mother is supplemented with tocotrienol (Roy et al., 2002) | |
| 2003 | Mouse; At nM concentrations α-tocotrienol, in contrast with α-tocopherol, protects against glutamate-induced neuronal death by suppressing inducible 12-lipoxygenase activation (Khanna et al., 2003) | |
| 2003 | Mouse; Injected α-tocotrienol decreased the size of the cerebral infarcts 1 day after stroke; γ-tocotrienol and delta- tocotrienol did not protect (Mishima et al., 2003) | |
| 2003 | Human; Tocotrienols induced IKBKAP expression: a possible therapy for familial dysautonomia (Anderson et al., 2003) | |
| 2004 | Rat; α-Tocotrienol provided the most potent neuroprotection among vitamin E analogs on cultured striatal neurons (Osakada et al., 2004) | |
| Hypocholesterolemic | 1986 | Chicken; Three double bonds in the isoprenoid chain essential for the inhibition of cholesterogenesis; tocopherols do not share this property (Qureshi et al., 1986) |
| 1991 |
Human; Lowered serum cholesterol in hypercholesterolemics (Qureshi et al., 1991b); lowered both serum total cholesterol (TC) and low-density-lipoprotein cholesterol (Tan et al., 1991)
Pigs; Reduced plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias (Qureshi et al., 1991a) |
|
| 1992 | In vitro; Post-transcriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis (Pearce et al., 1992) | |
| 1993 | Regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl- coenzyme A reductase (Parker et al., 1993) | |
| 1994 | HepG2; The farnesyl side chain and the methyl/hydroxy substitution pattern of gamma-tocotrienol responsible for HMG CoA reductase suppression (Pearce et al., 1994) | |
| 1995 | isoprenoid-mediated suppression of mevalonate synthesis depletes tumor tissues of two intermediate products, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are incorporated post-translationally into growth control- associated proteins (Elson and Qureshi, 1995) | |
| 1995 | Human; Lowered plasma cholesterol level in hypercholesterolemic subjects (Qureshi et al., 1995) | |
| 2001 | Chicken; The effects of a tocotrienol/lovastatin combination were no greater than that of tocotrienol alone, indicating that tocotrienol produced a maximum cholesterol lowering effect (Qureshi and Peterson, 2001) | |
| 2001 | Swine; Tocotrienols suppress cholesterogenesis in hereditary hypercholesterolemic swine (Qureshi et al., 2001a) | |
| 2001 | Human; Tocotrienol, not tocopherol, hypocholesterolemic in humans; claimed that tocotrienol is converted to tocopherol in vivo (Qureshi et al., 2001c) | |
| 2002 | Human; Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction of rice bran in hypercholesterolemic humans (Qureshi et al., 2002) | |
| 2002 | Hamster; Tocotrienols lower total cholesterol and low density lipoprotein plasma levels (Raederstorff et al., 2002) | |
| 2003 | Rat; Suppression of hypercholesterolaemia in rats by tocotrienol-rich fraction isolated from rice bran oil (Iqbal et al., 2003) | |
| ApoB level reduction in hypercholesterolemic subjects | 1999 | Human; in HepG2 cells tocotrienol (not tocopherol) stimulates apoB degradation possibly as the result of decreased apoB translocation into the endoplasmic reticulum lumen (Theriault et al., 1999) |
| Anti-hypertensive | 1992 | Rat; Depressed (better than α-tocopherol) age-related increase in the systolic blood pressure of spontaneously hypertensive rats (Koba et al., 1992) |
| Hypocholesterolemic and antioxidant | 1993 | Rat; spares plasma tocopherol (Watkins et al., 1993) |
| Lowering blood pressure; antioxidant | 1999 | SHR; Supplement of γ-tocotrienol may prevent increased blood pressure, reduce lipid peroxides in plasma and blood vessels and enhanced total antioxidant status (Newaz and Nawal, 1999) |
| Antioxidant | 1991 | In vitro; Better than α-tocopherol (Serbinova et al., 1991) |
| 1992 | In vitro; Facilitates antioxidant recycling (Kagan et al., 1992) | |
| 1993 | In vitro; Tocotrienol is better than tocopherol; tocotrienol is located closer to the cell membrane surface (Suzuki et al., 1993) | |
| 1993 | Human; Dietary tocotrienols become incorporated into circulating human lipoproteins where they react with peroxyl radicals as efficiently as the corresponding tocopherol isomers (Suarna et al., 1993) | |
| 1995 | Rat; Protects brain against oxidative damage (Kamat and Devasagayam, 1995) | |
| 1995 | Human; Controls the course of carotid atherosclerosis (Tomeo et al., 1995) | |
| 2002 | Human; α-Tocotrienol is more potent than α-tocopherol in protecting against free radical-induced impairment of erythrocyte deformability (Begum and Terao, 2002) | |
| 2002 | Rat; Comparable effects of a tocotrienol-rich fraction and tocopherol in aspirin-induced lipid peroxidation mediated gastric lesions (Nafeeza et al., 2002) | |
| 2003 | Rat; Antioxidant effects of γ-tocotrienol in spontaneously hypertensive rats (Newaz et al., 2003) | |
| 2003 | Tocopherols and tocotrienols have comparable antioxidant properties; Some of the vitamin E formulations tested showed antioxidant activities superior to d-alpha-tocopherol (Naguib et al., 2003) | |
| 2003 | The corresponding tocopherols and tocotrienols exert comparable antioxidant activity; tocotrienols are more readily transferred between the membranes and incorporated into the membranes than tocopherols (Yoshida et al., 2003) | |
| 2003 | Human; Topical α-tocotrienol supplementation inhibits lipid peroxidation in human skin (Weber et al., 2003) | |
| 2004 | Human; Lack of oxidative stress in a selenium deficient area in Ivory Coast Potential nutritional antioxidant role of crude palm oil (Tiahou et al., 2004) | |
| 2004 | Rat; Palm oil tocotrienol mixture better than α-tocopherol acetate in protecting bones against free-radical induced elevation of bone-resorbing cytokines (Soelaiman et al., 2004) | |
| 2004 | Mice; Ricetrienol exerted a protective effect against oxidative damage in diabetes mellitus (Kanaya et al., 2004) | |
| Antiaging/antioxidant | 2000 | C. elegans; Tocotrienol, not tocopherol, administration reduced the accumulation of protein carbonyl and consequently extended the mean life span but not the maximum life span (Adachi and Ishii, 2000). |
| Anti-cancer | 1989 | Mouse; Intraperitoneally injected tocotrienol prevented transplanted tumors (Komiyama et al., 1989) |
| 1989 | Rat; Tocotrienol-rich palm oil prevented chemically-induced mammary tumorigenesis (Sundram et al., 1989) | |
| 1991 | Rat; Tocotrienol., but not tocopherol, was chemopreventive in mammary tumor model (Gould et al., 1991) | |
| 1991 | Rat; Tocotrienol. chemopreventive in hepatic tumor model (Ngah et al., 1991) | |
| 1993 | Rat; Tocotrienol. chemopreventive in hepatic tumor model (Rahmat et al., 1993) | |
| 1994 | Human; Suppresses activation of Epstein-Barr virus early antigen expression in PMA-activated lymphoblastoid Raji cells (Goh et al., 1994) | |
| 1995 | Human; Tocotrienol, not tocopherol, suppresses growth of a human breast cancer cell line in culture (Nesaretnam et al., 1995) | |
| 1997 |
Human; Inhibited proliferation of estrogen receptor-negative MDA-MB-435 and -positive MCF-7 breast cancer cells (Guthrie et al., 1997)
Mouse; Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo (He et al., 1997) |
|
| 1998 | Human; Inhibit the growth of human breast cancer cells irrespective of estrogen receptor status (Nesaretnam et al., 1998) | |
| 1999 | Human; Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids (Mo and Elson, 1999) | |
| 1999 | Human; Naturally occurring tocotrienols and RRR-δ-tocopherol are effective apoptotic inducers for human breast cancer cells (Yu et al., 1999) | |
| 2000 | Human; Tocotrienols inhibit growth of ZR-75-1 breast cancer cells (Nesaretnam et al., 2000) | |
| 2000 | Mouse; Highly potent γ– and δ-tocotrienol isoforms may play a physiological role in modulating normal mammary gland growth, function, and remodeling (McIntyre et al., 2000b) | |
| 2000 | Mouse; highly malignant breast cancer cells were the most sensitive, whereas the preneoplastic cells were the least sensitive to the antiproliferative and apoptotic effects of tocotrienols (McIntyre et al., 2000a) | |
| 2001 | Mouse; Tocotrienols are significantly more potent than tocopherols in suppressing EGF-dependent normal mammary epithelial cell growth. The inhibitory effects of specific tocopherol and tocotrienol isoforms on EGF-dependent normal mammary epithelial cell mitogenesis occurs downstream from the EGF-receptor and appears to be mediated, at least in part, by a reduction in PKCα activation (Sylvester et al., 2001) | |
| 2002 | Mouse; Antiproliferative effects of tocotrienols in preneoplastic mammary epithelial cells do not reflect a reduction in EGF- receptor mitogenic responsiveness, but rather, result from an inhibition in early post-receptor events involved in cAMP production upstream from EGF-dependent MAPK and phosphoinositide 3-kinase/Akt mitogenic signaling (Sylvester et al., 2002) | |
| 2003 | Rat; Suppression of 7,12-dimethylbenz[alpha]anthracene-induced carcinogenesis by tocotrienol-rich fraction isolated from rice bran oil (Iqbal et al., 2003) | |
| 2003 | Mouse; Tocotrienol-induced apoptosis in mammary cancer cells is mediated through activation of the caspase-8 signaling pathway and is independent of caspase-9 activation (Shah et al., 2003) | |
| 2004 | Mouse; Tocotrienol-induces caspase-8 activation, unrelated to death receptor apoptotic signaling, in neoplastic mammary epithelial cells (Shah and Sylvester, 2004) | |
| 2004 | Rat; Tocotrienol induces apoptosis in dRLh-84 hepatoma cells (Sakai et al., 2004) | |
| 2004 | Rat; Tocotrienol-rich fraction isolated from rice bran oil suppressed diethylnitrosamine and 2-acetylaminofluorene-induced hepatocarcinogenesis (Iqbal et al., 2004) | |
| 2004 | Human; Tocotrienol disrupts mitochondrial function and causes apoptosis of breast cancer cells (Takahashi and Loo, 2004) | |
| 2004 | Human; Pro-apoptotic properties of δ-tocotrienol) in breast cancer cells (Shun et al., 2004) | |
| 2004 | Human; Supplementation of tocotrienol rich fraction of palm oil significantly and specifically affected MCF-7 cell response after tumor formation in vivo by an antioxidant-independent mechanism (Nesaretnam et al., 2004) | |
| 2004 | Human; Tocotrienol-rich fraction of palm oil activated p53, modulated Bax/Bcl2 ratio and induced apoptosis independent of cell cycle association in colorectal cancer RKO cells (Agarwal et al., 2004) | |
| Modulating normal mammary gland growth, function, and remodeling | 2000 | Mouse; Mammary epithelial cells more easily or preferentially took up tocotrienols as compared to tocopherols (McIntyre et al., 2000b) |
| Antiangiogenic | 2004 | Human/Chicken; Tocotrienol, not tocopherol, inhibited angiogenesis and telomerase activity (Nakagawa et al., 2004) |
| 2004 | Bovine; Tocotrienol, not tocopherol, limited angiogenic responses in vitro (Miyazawa et al., 2004) | |
| 2003 | Bovine; Tocotrienol, but not tocopherol, inhibited both the proliferation and tube formation of aortic endothelial cells (Inokuchi et al., 2003) | |
| Antiproliferative and apoptotic | 2000 | Mouse; Preneoplastic and neoplastic mammary epithelial cells: α- and γ-tocopherol had no effect on cell proliferation (McIntyre et al., 2000a) |
| 2003 | Cancer cell lines; Not α-tocotrienol but γ-tocotrienol was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of gamma-tocotrienol by one isoprenyl unit increased its activity (Birringer et al., 2003) | |
| Hypocholesterolemic, antioxidant & antitumor | 2000 | Chicken; The number and position of methyl substituents in tocotrienols affect their hypocholesterolemic, antioxidant, and antitumor properties; tocotrienol better than α-tocopherol (Qureshi et al., 2000) |
| Anti-atherogenic | 2001 | Mouse; Palm tocotrienols protect ApoE +/− mice from diet-induced atheroma formation (Black et al., 2000) |
| 2001 | Mouse; Tocotrienols inhibit atherosclerotic lesions in ApoE-deficient mice (Qureshi et al., 2001b) | |
| Serum lipoproteins; platelet function | 1999 | Human; in men at risk for cardiovascular disease tocotrienol supplements used had no marked favorable effects (Mensink et al., 1999) |
| Anti-inflammatory | 2002 | Human; Tocotrienols inhibit monocyte-endothelial cell adhesion (Chao et al., 2002) |
| 2002 | Human; Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes (Theriault et al., 2002) | |
| 2003 | Human; The efficacy of tocotrienol for reduction of VCAM-1 expression and adhesion of THP-1 cells to HUVECs was 10- fold higher than that of tocopherol (Noguchi et al., 2003) | |
| Serum triglycerides | 1999 | Rat; Lower in tocotrienol fed; higher IgM productivity of spleen lymphocytes and IgA, IgG, and higher IgM productivity mesenteric lymph node lymphocytes (Kaku et al., 1999) |
| Immune function | 1999 | Rats; Feeding affects proliferation and function of spleen and mesenetric lymph node lymphocytes (Gu et al., 1999) |
| Transfer Protein | 1997 | α-Tocopherol transfer protein binds α-tocotrienol with 11% efficiency compared to α-tocopherol (Hosomi et al., 1997) |
| Lymphatic transport | 1996 | Rat; preferential absorption of α-tocotrienol compared to γ– and δ-tocotrienols and α-tocopherol (Ikeda et al., 1996) |
| Drug metabolism | 2002 | Tocotrienols inhibit human glutathione S-transferase P1-1 (van Haaften et al., 2002) |
| 2003 | Human; Vitamin E are able to activate gene expression via the pregnane X receptor (PXR), a nuclear receptor regulating a variety of drug metabolizing enzymes. Tocotrienols more potent than tocopherols (Landes et al., 2003) | |
| 2004 | In vitro; Tocotrienols activate the steroid and xenobiotic receptor, SXR, and selectively regulate expression of its target genes (Zhou et al., 2004) | |
| Eye | 2004 | Rat; Preferential uptake of topically applied tocotrienol, over tocopherol, by ocular tissues (Tanito et al., 2004) |
| Bone | 2002 | Rat; Tocotrienols are needed for normal bone calcification in growing female rats (Norazlina et al., 2002) |
| Obesity & Osteoporosis | 2004 | Rat; Tocotrienol, not tocopherol, has the potential to be utilized as a prophylactic agent in preventing side effects of long- term glucocorticoid use (Ima-Nirwana and Suhaniza, 2004) |
| Diabetes | 2002 | Rat; Tocotrienols-rich diet decreased advanced glycosylation end-products in non-diabetic rats and improved glycemic control in streptozotocin-induced diabetic rats (Wan Nazaimoon and Khalid, 2002) |
| Natriuretic function | 2000 | Rat; An oral administration of γ-tocotrienol increases plasma concentration of 2,7,8-trimethyl-2-(beta-carboxyethyl)-6- hydroxy chroman (LLU-alpha, gamma-CEHC), a natriuretic compound (Hattori et al., 2000) |
| 2003 | Rat; γ-Tocotrienol is a natriuretic hormone precursor (Saito et al., 2003) | |
| Bioavailability | 1996 | Mouse; Supplemented tocotrienol not detected in the brain (Podda et al., 1996). See 2002* below. |
| 2000 | Human; Following supplementation, ~1μM tocotrienol detected in human plasma (O'Byrne et al., 2000) | |
| 2000 | Rat; The skin is a unique tissue in respect to its ability to discriminate between various vitamin E analogs; it preferentially uptakes dietary tocotrienols (Ikeda et al., 2000) | |
| 2001 | Humans; Increased absorption of the tocotrienols in the fed versus fasted state (Yap et al., 2001) | |
| 2001 | Humans; Tocotrienols, like tocopherols, are metabolized to CEHC; however, the quantities excreted in human urine are small in relation to dose size (Lodge et al., 2001) | |
| 2001 | Rat; Dietary sesame seeds elevate the tissue concentrations of orally taken tocopherols and tocotrienols (Ikeda et al., 2001) | |
| 2002* | Rat; Oral tocotrienol crosses the blood-brain barrier to reach brain tissue; more so for fetal brain while pregnant mother is supplemented with tocotrienol (Roy et al., 2002) | |
| 2002 | Human; In HepG2 cells, tocotrienols are metabolized essentially like tocopherols, i.e., by β-oxidation followed by β- oxidation of the side chain. Quantitatively, tocotrienols are degraded to a larger extent than tocopherols (Birringer et al., 2002) | |
| 2002 | Rat; Sesame lignans added to diet increased plasma and tissue concentrations of supplemented tocotrienols (Yamashita et al., 2002) | |
| 2002 | Rat;In epididymal adipose, renal adipose, subcutaneous adipose and brown adipose tissues and in the heart, the tocotrienol levels were maintained or increased for 24 h after intragastric administration. In the serum, liver, mesenteric lymph node, spleen and lungs, the tocotrienol levels were highest 8 h after the administration (Okabe et al., 2002) | |
| 2003 | Rat; Dietary α-tocopherol decreases α-tocotrienol but not γ-tocotrienol concentration in rats (Ikeda et al., 2003) | |
| 2003 | Tocotrienols are more readily transferred between the membranes and incorporated into the membranes than tocopherols (Yoshida et al., 2003) | |
| 2003 | Human; α-Tocotrienol accumulate in endothelial cells to levels approximately 10-fold greater than that of α-tocopherol (Noguchi et al., 2003) | |
| 2003 | Rat; Of the three tocotrienols, α-tocotrienol had the highest oral bioavailability, at about 27.7+/−9.2%, compared with γ– and δ-tocotrienols, which had values of 9.1+/−2.4% and 8.5+/−3.5%, respectively. Tocotrienols were found to be negligibly absorbed when administered intraperitoneally and intramuscularly (Yap et al., 2003) | |
| 2003 | Human; The t1/2 of tocotrienols is short, ranging from 3.8–4.4 h for γ – and α-tocotrienol (Schwedhelm et al., 2003) | |
| 2004 | Human; Following the intervention with palm vitamin E, tocotrienols are detected in total blood plasma, TRP, LDL and HDL. Tocotrienols appeared in the blood stream at 2h interval & disappeared within 24 h. Tocotrienols concentration in total plasma plasma, TRP & LDL peaked between 4 to 6 h; in HDL, tocotrienol concentrations peaked at 8 h after supplementation. α-tocopherol was the major vitamin E detected in plasma. Tocotrienols have a very short duration of absorption & distribution in circulating blood (Fairus et al., 2004). |
CEHC, carboxyethyl-hydroxychromans; EGF, epidermal growth factor; HDL, high density lipoprotein; HMG CoA reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HUVEC, human umbilical vein (derived) endothelial cells; IKBKAP, gene encoding IkappaB kinase complex-associated protein; LDL, low density lipoprotein; SHR, spontaneously hypertensive rats; TRP, triglyceride rich particles.