Vitamin E Tocotrienols: the next generation antioxidant and anti-inflammatory nutrient – Dr Bradley McEwen
Chronic diseases are the leading cause of morbidity and mortality worldwide, accounting for approximately 60% of all deaths.¹ Optimum nutrition is fundamental for the management and prevention of chronic disease. Vitamin E has been prescribed for various health conditions, but mainly in the form of tocopherols. This article aims to shed light on the health benefits of tocotrienols, particularly those of antioxidant, anti-inflammatory and cholesterol-lowering properties.
What are tocotrienols?
Vitamin E was discovered in green leafy vegetables in 1922.³ Vitamin E was named tocopherol in 1924 and synthesised in 1938.5 Vitamin E tocopherol was named the fertility vitamin. The name comes from the Greek word tokos, meaning childbirth, and phero, meaning to bring forth, and the ol ending was added to indicate the alcohol properties of this molecule.4 Vitamin E is a fat-soluble vitamin.4 Vitamin E has eight different isoforms that belong to two categories, tocopherols and tocotrienols. There are four saturated analogues of vitamin E (the tocopherols alpha (α), beta (β), gamma (γ) and delta (δ)) and four unsaturated analogues (alpha (α), beta (β), gamma (γ) and delta (δ)) which are the tocotrienols.4-9
Tocotrienols are more readily transferred and incorporated into cell membranes than tocopherols.5, 9 The unsaturated side chain of tocotrienols allows for more efficient penetration into tissues that have saturated fatty layers, such as the brain and liver,5 and distribute more evenly in lipid membranes.9
Tocotrienols have a higher peroxy radical-scavenging activity than tocopherols in liposomal membranes.5 Cellular uptake of tocotrienols is up to 70 times higher than that of tocopherols.5 The administration of 750 mg and 1000 mg of a tocotrienol mixture from Annatto (Bixa orellana) resulted in maximum plasma concentration levels at 3-4 hours for all isomers, whereas α-tocopherol peaked at 6 hours.10
Vitamin E deficiency has been associated with ataxia, Duchenne muscular dystrophy-like muscle degeneration, infertility,5 anaemia, impairment of immune response, retinopathy, and neuromuscular and neurological problems.11 Research indicates that tocotrienols exhibit antioxidant,5, 7, 12-15 anti-inflammatory,5, 7, 12, 13, 15 cholesterol-lowering,7, 13, 16 hypoglycaemic,12 hepatoprotective,12 nephroprotective,12 neuroprotective,4, 6, 8, 15, 17, 18 antiangiogenic,5 and immunomodulatory12 properties. Additionally, tocotrienols have potential in managing Alzheimer’s disease due to their antioxidant and anti-inflammatory effects.19, 20 The focus of this article is on the antioxidant, anti-inflammatory and cholesterol-lowering properties of tocotrienols.
Tocotrienols and oxidative stress
Oxidative stress occurs from the imbalance between reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and the body’s antioxidant defences.21 Oxidative stress and free radical damage are involved in the initiation and progression of numerous chronic conditions, such as cardiovascular diseases,21, 22 hypertension,22 atherosclerosis,22 chronic obstructive pulmonary diseases,21 asthma,22 chronic kidney disease,21 type 2 diabetes,21, 22 non-alcoholic fatty liver disease,23 neurodegenerative diseases,21 autoimmune diseases,22 cognitive conditions,21 macular degeneration,21 cancer,21, 22 sarcopenia,21 and frailty.21 Antioxidants play a vital role in scavenging free radicals, thus protecting the cells from oxidative damage.8
Tocotrienols have antioxidant properties.4-6, 15, 18, 24, 25 The antioxidant activities of tocotrienols are mediated through the induction of various antioxidant enzymes, such as superoxide dismutase and glutathione peroxidase.5 The antioxidant activity quenches free radicals, such as superoxide radicals.5 Tocotrienols reduce oxidative protein damage 4, 14 and lipid oxidation.11 Tocotrienols also protect monounsaturated and polyunsaturated fatty acids (PUFAs) from oxidation,11, 14 and are therefore beneficial when added to PUFA supplements such as Omega-3. Additionally, tocotrienols have been shown to have 40-60 times higher antioxidant activity against induced lipid peroxidation than tocopherols and 6.5 times better protection of cytochrome P-450 against oxidative damage than tocopherols.5
A randomised, double-blinded placebo-controlled study was undertaken to evaluate the effect of tocotrienols on DNA damage. Sixty-four subjects, aged 37-78 years, completed the study. A daily dose of 160 mg of tocotrienols was given for 6 months. A significant reduction in
DNA damage was found after 3 months (P < 0.01) and remained low at 6 months (P < 0.01).26
Tocotrienols and inflammation
Inflammation means “set on fire”.1 Inflammation is the immune system’s response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation. It acts by removing injurious stimuli and initiating the healing process.22 Inflammation and dysregulation of inflammatory pathways lead to the development of chronic diseases.1 It should be noted that inflammation is a defence mechanism that is vital to health.22 Acute inflammation is a part of innate immunity initiated by the immune cells that last only for a short period of time.1
Acute inflammation is the host defence against infections and allergens.1 However, if the inflammation continues and persists in magnitude or duration,27 the second stage of inflammation called chronic inflammation commences.1, 22, 27 This chronic stage of inflammations leads to chronic diseases, including arthritis,1, 22 cancer,1, 22 cardiovascular diseases,1, 22 atherosclerosis,22 type 2 diabetes,1 neurodegenerative diseases,1 neurological diseases,1 respiratory diseases,1 asthma,22 autoimmune diseases,22 non-alcoholic fatty liver disease,23 and bowel diseases.22
Research suggests that tocotrienols exhibit potent anti-inflammatory activity.5, 15, 28 Tocotrienols have been shown to suppress the expression of tumour necrosis factor-alpha (TNF-α), interleukins (such as IL-1, IL-6, IL-8), inducible nitric oxide synthase, and cyclo-oxygenase 2 (COX-2),5 all of which mediate inflammation.5
A study investigated the effect of gamma tocotrienols in patients with hypercholesterolaemia.29 Participants were given increasing doses of gamma- tocotrienols (125, 250, 500, 750 mg per day) for 4 weeks each during a 30-week study period. All doses significantly reduced serum nitric oxide, C-reactive protein, inflammatory cytokines (resistin, IL-1α, IL-12, IFN-γ), malondialdehyde, and gamma-glutamyl-transferase. Total antioxidant status was increased.29
A randomised, double-blind, placebo-controlled study investigated gamma tocotrienols 300mg or placebo twice daily in patients with non-alcoholic fatty liver disease for 12 weeks.23 After 12 weeks of supplementation, gamma-tocotrienols decreased serum aminotransferases and hs-CRP, along with malondialdehyde (a marker of oxidative stress), and fatty liver index score.23
Tocotrienols and cholesterol
Hypercholesterolaemia is amongst the most common conditions encountered in clinical practice.30 Hypercholesterolaemia is a major risk factor for cardiovascular disease, having direct negative effects on the myocardium itself, in addition to the development of atherosclerosis.31 Hypercholesterolaemia is involved in myocardial ischaemia/reperfusion injury and causes endothelial dysfunction.31 Tocotrienols have cholesterol-lowering properties.4, 5 The mechanism of action is via inhibition of HMG-CoA reductase, an enzyme that is rate-limiting in the pathway to cholesterol biosynthesis.4, 5, 14, 28 A study on patients with hypercholesterolaemia found that 250 mg daily for 4 weeks found significant reductions in total cholesterol (15%), LDL-cholesterol (18%), and triglycerides (14%).16
Optimum nutrition plays a fundamental role in the prevention and management of chronic diseases. Tocotrienols have antioxidant, anti-inflammatory, cholesterol-lowering, hepatoprotective and neuroprotective properties and have the potential to play a major role in clinical practice, especially in the management of chronic disease. Should tocotrienols be a foundation of patient management? That is a question that needs further exploring.
Written By: Bradley McEwen | PhD, MHSc (Hum Nutr), BHSc, ND (Adv), DBM, DNutr, DSM, M.ATMS, Naturopath, Nutritionist, and
Mentor. Adjunct Senior Lecturer, School of Health and Human Sciences, Southern Cross University.
References available on request