Abstract and Introduction
Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley, and certain types of nuts and grains. Like tocopherols, tocotrienols are also of four types viz. alpha, beta, gamma and delta. Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. Tocopherols are lipophilic in nature and are found in association with lipoproteins, fat deposits and cellular membranes and protect the polyunsaturated fatty acids from peroxidation reactions. The unsaturated chain of tocotrienol allows an efficient penetration into tissues that have saturated fatty layers such as the brain and liver. Recent mechanistic studies indicate that other forms of vitamin E, such as γ-tocopherol, δ-tocopherol, and γ-tocotrienol, have unique antioxidant and anti-inflammatory properties that are superior to those of α-tocopherol against chronic diseases. These forms scavenge reactive nitrogen species, inhibit cyclooxygenase- and 5-lipoxygenase-catalyzed eicosanoids and suppress proinflammatory signalling, such as NF-κB and STAT. The animal and human studies show tocotrienols may be useful against inflammation-associated diseases. Many of the functions of tocotrienols are related to its antioxidant properties and its varied effects are due to it behaving as a signalling molecule. Tocotrienols exhibit biological activities that are also exhibited by tocopherols, such as neuroprotective, anti-cancer, anti-inflammatory and cholesterol lowering properties. Hence, effort has been made to compile the different functions and properties of tocotrienols in experimental model systems and humans. This article constitutes an in-depth review of the pharmacology, metabolism, toxicology and biosafety aspects of tocotrienols. Tocotrienols are detectable at appreciable levels in the plasma after supplementations. However, there is inadequate data on the plasma concentrations of tocotrienols that are sufficient to demonstrate significant physiological effect and biodistribution studies show their accumulation in vital organs of the body. Considering the wide range of benefits that tocotrienols possesses against some common human ailments and having a promising potential, the experimental analysis accounts for about a small fraction of all vitamin E research. The current state of knowledge deserves further investigation into this lesser known form of vitamin E.
Evans and Bishop, in 1922, discovered that dietary supplements with alfalfa leaves (rich in vitamin E) prevent placental hemorrhage and reverse dietary sterility in rats. Evans and his associates isolated the compounds of vitamin E family and named them tocopherols (Greek: Tocos-child birth; pheros- to bear; ol-alcohol). While alpha-tocopherol was the first vitamin E isomer to be recognized, eight chemically distinct isomers are now known, consisting of alpha (α), beta (β), gamma (γ) and delta (δ)-tocopherols and α, β, γ and δ-tocotrienols (T3), all of them are referred to as vitamin E. The tocopherols are saturated forms of vitamin E, whereas the tocotrienols are unsaturated and possess an isoprenoid side chain (Table 1). The name "tocotrienol" was first suggested by Dr. Banyan, for the isomers of vitamin E, with isoprenoid side chain present in nature, when isolated from the latex of the rubber plant, Havea brasiliensis. Tocotrienols attracted no real attention until the 1980's and 1990's when their cholesterol-lowering potential and anticancer effects were described.[5,6] This review article will take a closer look at the various functions of tocotrienol by providing numerous potential evidences on how it may be protective against these chronic diseases. Tocotrienols are found in certain cereals and vegetables such as palm oil, rice bran oil, coconut oil, barley germ, wheat germ and annatto.[7,8] Palm oil and rice bran oil contain particularly higher amounts of tocotrienols (940 mg/kg and 465 mg/kg, respectively). Other sources of tocotrienols include grape fruit seed oil, oats, hazelnuts, maize, olive oil, Buckthorn berry, rye, flax seed oil, poppy seed oil and sunflower oil.
Tocotrienols possess powerful neuroprotective, antioxidant, anti-cancer and cholesterol lowering properties that often differ from the properties of tocopherols. Micromolar amounts of tocotrienol suppress the activity of HMG-CoA reductase, the hepatic enzyme responsible for the synthesis of cholesterol.[11,12] Tocotrienols are thought to have more potent antioxidant properties than α-tocopherol.[13,14] The unsaturated side chain of tocotrienol allows for more efficient penetration into tissues that have saturated fatty layers such as the brain and liver. Experimental research examining the antioxidant, free radical scavenging, effects of tocopherol and tocotrienols have found that tocotrienols appear superior due to their better distribution in the lipid layers of the cell membrane. One major conclusion often used to undermine tocotrienol research is the relative inferiority of the bioavailability of orally taken tocotrienols as compared to that of α-tocopherol. The hepatic α-tocopherol transfer protein (α-TTP), together with the tocopherol-associated proteins (TAP) is responsible for the endogenous accumulation of natural α-tocopherol.
Tocotrienols are absorbed, in the same way as other vitamin E compounds, alongwith fat, in the small intestine, after being cleaved by the enzyme esterase, located in the stomach lining. Bile salts are necessary for the absorption. It is then packaged into chylomicrons and then transported in the lymphatic system. The α-tocotrienol appears to be better absorbed than the other forms of tocotrienol. In the bloodstream, tocotrienols are exposed to the oxidative free radicals and therefore perform most of their antioxidant activity. Tissue uptake takes place either with the help of lipoprotein lipases, digesting the lipoprotein constituents, or by receptor mediated endocytosis of lipoprotein. Lipoprotein lipase degrades lipoproteins to remnant particles which are then taken up by liver or peripheral tissues by receptor mediated endocytosis. Tocotrienols enter a variety of different tissue types, with adipose and adrenal gland having the highest levels. Vitamins can be stored in the tissue for long periods of time because of their exceedingly slow turnover rate. Vitamin E is oxidized after it has performed its antioxidant function. It is converted to its hydroquinone form in a P450 dependent manner before being eliminated from the body through faeces. Hydroquinone form binds with glucuronic acid and mixes with bile for removal through faeces. Despite the promising potential of tocotrienol, the experimental analysis accounts for only a small fraction of all vitamin E research. However, biologists are increasingly realizing the importance of this minor and unique vitamin E isomer.
Various minerals and vitamins are present in a variety of food products and available as dietary supplements. Selenium (Se) is an essential micronutrient that occurs predominantly as selenomethionine (SeMet), whereas vitamin E (or a-tocopherol) is a fat-soluble physiological antioxidant, both of which are required for normal health.[17–19] The Se and vitamin E are essential components of the human diet and have been studied as antioxidants and potential therapeutic agents for a variety of human diseases. Various formulations of Se and vitamin E have been shown to possess a therapeutic and preventive effect against prostate cancer (PCa) cells.
The motivation for the use of vitamin E and Se for the prevention of PCa comes from clinical trial data. Vitamin E was shown to be a promising candidate for PCa prevention in the α-Tocopherol β-Carotene Cancer Prevention Study, a controlled smoking trial where α-tocopherol reduced PCa incidence by 32% and mortality by 41%. The SUpplementation en VItamines et Mineraux AntioXidants (SUVIMAX) study found a significant reduction in PCa rates among men receiving a multivitamin containing 30 mg vitamin E, although the protective effect could not be attributed to any specific micronutrient. In contrast, the Heart Outcomes Prevention Evaluation (HOPE) trial, the Heart Protection Study, the NIH-AARP Diet and Health Study and the Cancer Prevention Study II Nutrition Cohort donot support a general protective effect of α-tocopherol supplement use for PCa prevention.[23–26]
Therefore, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), was designed to test a prostate cancer chemoprevention hypothesis using oral Se and vitamin E supplementation in disease-free volunteers. Initiated in 2001, the SELECT was a phase III, randomized, placebo-controlled human trial to investigate the PCa chemopreventive effects of Se, vitamin E or their combination. SELECT was among the largest clinical chemoprevention trials ever, with an enrollment of more than 35,000 men and an intended follow-up of up to 12 years. SELECT was predicated on basic and clinical research including secondary endpoint data from cancer prevention studies that implied Se and vitamin E supplements could be useful in reducing PCa risk. However, the trial was prematurely terminated in 2008, 18 months before its intended minimum follow-up length. The Se and vitamin E doses and formulations used in SELECT were found to be ineffective, and concern was raised about a possible trend in developing type 2 diabetes mellitus among the study participants taking Se. Further, a statistically nonsignificant increased risk of PCa was also seen in the vitamin E group participants. Unfortunately, despite the perceived suitability of PCa for chemoprevention and the considerable evidence suggesting the usefulness of Se and vitamin E for PCa prevention, SELECT failed to show a positive effect. Hence, the SELECT trial was terminated early because of the safety concerns and negative data for the formulations and doses given.
The biological activity of vitamin E has generally been associated with its well-defined antioxidant property, specifically against lipid peroxidation in biological membranes. In the vitamin E group, a-tocopherol is considered to be the most active form. Moreover, tocotrienol has been shown to possess novel hypocholesterolemic effects together with an ability to reduce the atherogenic apolipoprotein B and lipoprotein(a) plasma levels. In addition, tocotrienol has been suggested to have an anti-thrombotic and anti-tumor effect indicating that tocotrienol may serve as an effective agent in the prevention and/or treatment of cardiovascular disease and cancer. The physiological activity of tocotrienol suggests it to be superior than a-tocopherol in many pathophysiological conditions. Hence, the role of tocotrienol in the prevention of cardiovascular disease and cancer may have significant clinical implications. Additional studies on its mechanism of action, as well as, long-term intervention studies from the pharmacological point-of-view are required to elucidate its function.
Nutr Metab. 2014;11(52) © 2014 BioMed Central, Ltd.