Tocotrienol

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General chemical structure of tocotrienols. alpha(a)-Tocotrienol: R1 = Me, R2 = Me, R3 = Me; beta(b)-Tocotrienol: R1 = Me, R2 = H, R3= Me; gamma(g)-Tocotrienol: R1 = H, R2 = Me, R3= Me; delta(d)-Tocotrienol: R1 = H, R2 = H, R3= Me Tocotrienols.svg
General chemical structure of tocotrienols. alpha(α)-Tocotrienol: R1 = Me, R2 = Me, R3 = Me; beta(β)-Tocotrienol: R1 = Me, R2 = H, R3= Me; gamma(γ)-Tocotrienol: R1 = H, R2 = Me, R3= Me; delta(δ)-Tocotrienol: R1 = H, R2 = H, R3= Me

The vitamin E family comprises four tocotrienols (alpha, beta, gamma, delta) and four tocopherols (alpha, beta, gamma, delta). The critical chemical structural difference between tocotrienols and tocopherols is that tocotrienols have unsaturated isoprenoid side chains with three carbon-carbon double bonds versus saturated side chains for tocopherols (see Figure). [1] [2]

Contents

Tocotrienols are compounds naturally occurring at higher levels in some vegetable oils, including palm oil, rice bran oil, wheat germ, barley, saw palmetto, annatto, and certain other types of seeds, nuts and grains, and the oils derived from them. [3] [4]

Chemically, different analogues of vitamin E all show some activity as a chemical antioxidant, [5] but do not all have the same vitamin E equivalence. Tocotrienols demonstrate activity depending on the type of antioxidant performance being measured. [6] All tocotrienols have some physical antioxidant activity due to an ability to donate a hydrogen atom (a proton plus electron) from the hydroxyl group on the chromanol ring, to free radical and reactive oxygen species. Historically studies of tocotrienols account for less than 1% of all research into vitamin E. [7] Tocotrienols are generally well tolerated and without significant side effects.

Health effects

The Food and Nutrition Board of the Institute of Medicine of the United States National Academy of Sciences does not define a Recommended Dietary Allowance or Adequate Intake for tocotrienols. [8]

Brain

A review of human studies in middle-aged and elderly stated "Evidence from prospective and case-control studies suggested that increased blood levels of tocotrienols were associated with favorable cognitive function outcomes." The review qualified this statement by noting that randomized, controlled clinical trials were needed to evaluate these observations. [9]

Heart disease

Tocotrienols have been linked to improved markers of heart disease. [10]

History

The discovery of tocotrienols was first reported by Pennock and Whittle in 1964, describing the isolation of tocotrienols from rubber. [11] The biological significance of tocotrienols was clearly delineated in the early 1980s, when its ability to lower cholesterol was first reported by Asaf Qureshi and Elson in the Journal of Medicinal Chemistry. [12] During the 1990s, the anti-cancer properties of tocopherols and tocotrienols began to be delineated. [13] The current commercial sources of tocotrienol are rice and palm. [14] Other natural tocotrienol sources include rice bran oil, coconut oil, cocoa butter, barley, and wheat germ. [15] Tocotrienols are safe and human studies show no adverse effects with consumption of 240 mg/day for 48 months. [16] Tocotrienol rich fractions from rice, palm, or annatto, used in nutritional supplements, functional foods, and anti-aging cosmetics, are available in the market at 20%, 35%, 50%, and 70% total vitamin E content.

Etymology

Tocotrienols are named by analogy to tocopherols (from Greek words meaning to bear a pregnancy (see tocopherol); but with this word changed to include the chemical difference that tocotrienols are trienes, meaning that they share identical structure with the tocopherols except for the addition of the three double bonds to their side chains.

Comparison to tocopherols

Tocotrienols have only a single chiral center—the 2' carbon on the chromanol ring, which is where the isoprenoid tail is attached. Unlike the tocopherols, which have additional chiral centers along their saturated tail chain, the unsaturated chain of the tocotrienols instead have double-bonds at this sites. Tocotrienols extracted from plants are always dextrorotatory stereoisomers, signified as d-tocotrienols. In theory, (levorotatory; l-tocotrienol) forms of tocotrienols could exist as well, which would have a 2S rather than 2R configuration at the molecules' single chiral center, but unlike synthetic, dl-alpha-tocopherol, the marketed tocotrienol dietary supplements are all d-tocotrienol extracts from palm or annatto oils.[ citation needed ]

Tocotrienol studies confirm anti-oxidation, [17] anti-inflammatory potentials and suggest anti-cancer effects [18] [19] better than the common forms of tocopherol due to their chemical structure. Scientists have suggested tocotrienols are better antioxidants than tocopherols. [20] [21] [22] [23] It has been proposed that the unsaturated side-chain in tocotrienols causes them to penetrate tissues with saturated fatty layers more efficiently than tocopherol. [24] Lipid ORAC values are highest for δ-tocotrienol. [25] However that study also says: "Regarding α-tocopherol equivalent antioxidant capacity, no significant differences in the antioxidant activity of all vitamin E isoforms were found."

Metabolism and bioavailability

Absorption and distribution

Tocotrienols are primarily administered orally and, due to their lipophilic nature, their absorption is significantly enhanced when taken with a fat-rich diet. These compounds are mainly absorbed in the small intestine, with absorption depending on adequate pancreatic function, bile secretion, and micelle formation in the intestines. Upon administration, tocotrienols are distributed throughout the body, with higher concentrations observed in plasma and adipose tissues. [26]

Bioavailability factors

The short half-lives of tocotrienols are attributed to their low binding affinity for α-TTP, which maintains plasma levels of tocopherols. Specifically, α-tocopherol has a significantly higher binding affinity for α-TTP compared to tocotrienols. Relative to α-tocopherol's affinity, α-tocotrienol has about 9%, δ-tocotrienol 12%, and ɤ-tocotrienol 2% affinity for α-TTP. Consequently, δ-tocotrienol remains in plasma for a longer duration, offering greater bioavailability and slower biotransformation compared to other isomers. Human studies have indicated that δ-tocotrienol has a bioavailability of 28%, while ɤ- and α- isomers exhibit 9%. [26]

Metabolism and excretion

Tocotrienols are primarily metabolized in the liver, undergoing ω-hydroxylation by the enzymes CYP3A4 and CYP4F2, followed by β-oxidation. The final metabolites, carboxyethyl-hydroxychromanols (CEHC) and carboxymethylbutyl hydroxychroman (CMBHC), are readily excreted in urine. [26]

Sources

In nature, tocotrienols are present in many plants and fruits. The oil palm fruit ( Elaeis guineensis ) is particularly high in tocotrienols, primarily gamma-tocotrienol, alpha-tocotrienol and delta-tocotrienol. Other cultivated plants high in tocotrienols includes rice, wheat, barley, rye and oat. [27]

Research

Radiation countermeasures

Following exposure to gamma radiation, hematopoietic stem cells (HSCs) in the bone marrow, which are important for producing blood cells, rapidly undergo apoptosis (cell death). There are no known treatments for this acute effect of radiation. [28] Two studies conducted by the U.S. Armed Forces Radiobiology Research Institute (AFRRI) found that treatment with γ-tocotrienol or δ-tocotrienol enhanced survival of hematopoietic stem cells, which are essential for renewing the body's supply of blood cells. [28] [29] Based on these successful results of studies in mice, γ-tocotrienol is being studied for its safety and efficacy as a radioprotective measure in nonhuman primates. [30] No human trials have yet been completed.

Further reading

Related Research Articles

Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. Autoxidation leads to degradation of organic compounds, including living matter. Antioxidants are frequently added to industrial products, such as polymers, fuels, and lubricants, to extend their usable lifetimes. Foods are also treated with antioxidants to forestall spoilage, in particular the rancidification of oils and fats. In cells, antioxidants such as glutathione, mycothiol, or bacillithiol, and enzyme systems like superoxide dismutase, can prevent damage from oxidative stress.

<span class="mw-page-title-main">Carotene</span> Class of compounds

The term carotene (also carotin, from the Latin carota, "carrot") is used for many related unsaturated hydrocarbon substances having the formula C40Hx, which are synthesized by plants but in general cannot be made by animals (with the exception of some aphids and spider mites which acquired the synthesizing genes from fungi). Carotenes are photosynthetic pigments important for photosynthesis. Carotenes contain no oxygen atoms. They absorb ultraviolet, violet, and blue light and scatter orange or red light, and (in low concentrations) yellow light.

Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitamin E, can cause nerve problems. Vitamin E is a fat-soluble antioxidant which may help protect cell membranes from reactive oxygen species. Worldwide, government organizations recommend adults consume in the range of 3 to 15 mg per day. As of 2016, consumption was below recommendations according to a worldwide summary of more than one hundred studies that reported a median dietary intake of 6.2 mg per day for alpha-tocopherol. Foods rich in vitamin E include seeds and nuts, seed oils, peanut butter, and vitamin E-fortified foods.

Tocopherols are a class of organic compounds comprising various methylated phenols, many of which have vitamin E activity. Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rats, it was named tocopherol, from Greek τόκοςtókos 'birth' and φέρεινphérein 'to bear or carry', that is 'to carry a pregnancy', with the ending -ol signifying its status as a chemical alcohol.

<span class="mw-page-title-main">Lipoic acid</span> Chemical compound

Lipoic acid (LA), also known as α-lipoic acid, alpha-lipoic acid (ALA) and thioctic acid, is an organosulfur compound derived from caprylic acid (octanoic acid). ALA, which is made in animals normally, is essential for aerobic metabolism. It is also available as a dietary supplement or pharmaceutical drug in some countries. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. Only the (R)-(+)-enantiomer (RLA) exists in nature. RLA is an essential cofactor of many processes.

Coenzyme Q<sub>10</sub> Biochemical cofactor and antioxidant

Coenzyme Q10 (CoQ10) also known as ubiquinone, is a naturally occurring biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, seed oils, vegetables, and dietary supplements. CoQ10 is found in many organisms, including animals and bacteria.

<span class="mw-page-title-main">Bran</span> Hard outer layers of cereal grain

Bran, also known as miller's bran, is the component of a cereal grain consisting of the hard layers - the combined aleurone and pericarp - surrounding the endosperm. Corn (maize) bran also includes the pedicel. Along with the germ, it is an integral part of whole grains, and is often produced as a byproduct of milling in the production of refined grains. Bran is highly nutritious, but is difficult to digest due to its high fiber content; its high fat content also reduces its shelf life as the oils/fats are prone to becoming rancid. As such, it is typically removed from whole grain during the refining process - e.g. in processing wheat grain into white flour, or refining brown rice into white rice.

β-Carotene Red-orange pigment of the terpenoids class

β-Carotene (beta-carotene) is an organic, strongly colored red-orange pigment abundant in fungi, plants, and fruits. It is a member of the carotenes, which are terpenoids (isoprenoids), synthesized biochemically from eight isoprene units and thus having 40 carbons.

<span class="mw-page-title-main">Herbert McLean Evans</span> American anatomist and embryologist

Herbert McLean Evans was an American anatomist and embryologist best known for co-discovering Vitamin E.

<span class="mw-page-title-main">Stanol ester</span> Class of chemical compounds

Stanol esters is a heterogeneous group of chemical compounds known to reduce the level of low-density lipoprotein (LDL) cholesterol in blood when ingested, though to a much lesser degree than prescription drugs such as statins. The starting material is phytosterols from plants. These are first hydrogenated to give a plant stanol which is then esterified with a mixture of fatty acids also derived from plants. Plant stanol esters are found naturally occurring in small quantities in fruits, vegetables, nuts, seeds, cereals, legumes, and vegetable oils.

<span class="mw-page-title-main">Oxidative stress</span> Free radical toxicity

Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O−
2, OH and H2O2. Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.

α-Tocopheryl acetate Vitamin

α-Tocopheryl acetate, also known as vitamin E acetate, is a form of vitamin E with D-Alpha Tocpheryl Acetate as the natural form and DL-Alpha Tocopheryl Acetate as the synthetic form. DL-indicates the synthetic form where as D- indicates the natural form. It is the ester of acetic acid and α-tocopherol.

<span class="mw-page-title-main">Campesterol</span> Chemical compound

Campesterol is a phytosterol whose chemical structure is similar to that of cholesterol, and is one of the ingredients for E number E499.

α-Tocopherol Chemical compound

α-Tocopherol (alpha-tocopherol) is a type of vitamin E. Its E number is "E307". Vitamin E exists in eight different forms, four tocopherols and four tocotrienols. All feature a chromane ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain which allows for penetration into biological membranes. Compared to the others, α-tocopherol is preferentially absorbed and accumulated in humans.

<span class="mw-page-title-main">Sea buckthorn oil</span> Vegetable oil

Sea buckthorn oil is a red-orange oil derived from sea buckthorn plants. The most commonly used species for this purpose is Hippophae rhamnoides. Species belonging to this genus accumulate lipids in the mesocarp, so the oil can be extracted from either the seeds or the pulp.

Vitamins occur in a variety of related forms known as vitamers. A vitamer of a particular vitamin is one of several related compounds that performs the functions of said vitamin and prevents the symptoms of deficiency of said vitamin.

<span class="mw-page-title-main">Selenium in biology</span> Use of Selenium by organisms

Selenium is an essential micronutrient for animals, though it is toxic in large doses. In plants, it sometimes occurs in toxic amounts as forage, e.g. locoweed. Selenium is a component of the amino acids selenocysteine and selenomethionine. In humans, selenium is a trace element nutrient that functions as cofactor for glutathione peroxidases and certain forms of thioredoxin reductase. Selenium-containing proteins are produced from inorganic selenium via the intermediacy of selenophosphate (PSeO33−).

β-Tocotrienol is a tocotrienol, a member of vitamin E family.

γ-Tocotrienol is one of the four types of tocotrienol, a type of vitamin E.

References

  1. ↑ Kamal-Eldin A, Appelqvist LA (July 1996). "The chemistry and antioxidant properties of tocopherols and tocotrienols". Lipids. 31 (7): 671–701. doi: 10.1007/BF02522884 . PMID   8827691. S2CID   4052785.
  2. ↑ Clarke MW, Burnett JR, Croft KD (2008). "Vitamin E in human health and disease". Critical Reviews in Clinical Laboratory Sciences. 45 (5): 417–50. doi:10.1080/10408360802118625. PMID   18712629. S2CID   85991655.
  3. ↑ Tan B, Watson RR, Preedy VR, eds. (2013). Tocotrienols: Vitamin E Beyond Tocopherols (2nd ed.). Boca Raton: CRC Press. ISBN   9781439884416.
  4. ↑ Sen CK, Rink C, Khanna S (June 2010). "Palm oil-derived natural vitamin E alpha-tocotrienol in brain health and disease". Journal of the American College of Nutrition. 29 (3 Suppl): 314S–323S. doi:10.1080/07315724.2010.10719846. PMC   3065441 . PMID   20823491.
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  6. ↑ Fu JY, Che HL, Tan DM, Teng KT (January 2014). "Bioavailability of tocotrienols: evidence in human studies". Nutrition & Metabolism. 11 (1): 5. doi: 10.1186/1743-7075-11-5 . PMC   3895660 . PMID   24410975.
  7. ↑ Sen CK, Khanna S, Roy S (2007). "Tocotrienols in health and disease: the other half of the natural vitamin E family". Molecular Aspects of Medicine. 28 (5–6): 692–728. doi:10.1016/j.mam.2007.03.001. PMC   2435257 . PMID   17507086.
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  9. ↑ Georgousopoulou EN, Panagiotakos DB, Mellor DD, Naumovski N (January 2017). "Tocotrienols, health and ageing: A systematic review" (PDF). Maturitas. 95: 55–60. doi:10.1016/j.maturitas.2016.11.003. PMID   27889054.
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  11. ↑ Dunphy PJ, Whittle KJ, Pennock JF, Morton RA (1965). "Identification and Estimation of Tocotrienols in Hevea Latex". Nature. 207 (4996): 521–522. Bibcode:1965Natur.207..521D. doi:10.1038/207521a0. S2CID   4214464.
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  13. ↑ Schauss AG (2008). "Tocotrienols: A Review". In Watson RR, Preedy VR (eds.). Tocotrienols: Vitamin E Beyond Tocopherols. CRC Press. p.  6. ISBN   978-1-4200-8037-7.
  14. ↑ Tan, B. and M.H. Saleh, Integrated process for recovery of carotenoids and tocotrienols from oil in USPTO 5,157,132. 1992
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  18. ↑ Constantinou C, Papas A, Constantinou AI (August 2008). "Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs". International Journal of Cancer. 123 (4): 739–52. doi: 10.1002/ijc.23689 . PMID   18512238. S2CID   3549712.
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  20. ↑ Müller L, Theile K, Böhm V (May 2010). "In vitro antioxidant activity of tocopherols and tocotrienols and comparison of vitamin E concentration and lipophilic antioxidant capacity in human plasma". Molecular Nutrition & Food Research. 54 (5): 731–42. doi:10.1002/mnfr.200900399. PMID   20333724.
  21. ↑ Yoshida Y, Niki E, Noguchi N (March 2003). "Comparative study on the action of tocopherols and tocotrienols as antioxidant: chemical and physical effects". Chemistry and Physics of Lipids. 123 (1): 63–75. doi:10.1016/S0009-3084(02)00164-0. PMID   12637165.
  22. ↑ Schaffer S, Müller WE, Eckert GP (February 2005). "Tocotrienols: constitutional effects in aging and disease". The Journal of Nutrition. 135 (2): 151–4. doi: 10.1093/jn/135.2.151 . PMID   15671205.
  23. ↑ Theriault A, Chao JT, Wang Q, Gapor A, Adeli K (July 1999). "Tocotrienol: a review of its therapeutic potential". Clinical Biochemistry. 32 (5): 309–19. doi:10.1016/S0009-9120(99)00027-2. PMID   10480444.
  24. ↑ Suzuki YJ, Tsuchiya M, Wassall SR, Choo YM, Govil G, Kagan VE, et al. (October 1993). "Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency". Biochemistry. 32 (40): 10692–9. doi:10.1021/bi00091a020. PMID   8399214.
  25. ↑ Müller L, Theile K, Böhm V (May 2010). "In vitro antioxidant activity of tocopherols and tocotrienols and comparison of vitamin E concentration and lipophilic antioxidant capacity in human plasma". Molecular Nutrition & Food Research. 54 (5): 731–42. doi:10.1002/mnfr.200900399. PMID   20333724.
  26. 1 2 3 Sharif M, Khan DA, Farhat K, Mudassar Noor, Mohammad Asghar Khan, Saima Rafique (2023-02-15). "Pharmacokinetics and bioavailability of tocotrienols in healthy human volunteers: a systematic review". Journal of the Pakistan Medical Association. 73 (3): 603–610. doi: 10.47391/JPMA.6008 . ISSN   0030-9982. PMID   36932765. S2CID   257423183.
  27. ↑ Tocopherol and tocotrienol contents of raw and processed fruits and vegetables in the United States diet p.199
  28. 1 2 Li XH, Fu D, Latif NH, Mullaney CP, Ney PH, Mog SR, et al. (December 2010). "Delta-tocotrienol protects mouse and human hematopoietic progenitors from gamma-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling". Haematologica. 95 (12): 1996–2004. doi:10.3324/haematol.2010.026492. PMC   2995556 . PMID   20823133.
  29. ↑ Kulkarni S, Ghosh SP, Satyamitra M, Mog S, Hieber K, Romanyukha L, et al. (June 2010). "Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation". Radiation Research. 173 (6): 738–47. Bibcode:2010RadR..173..738K. doi:10.1667/RR1824.1. PMID   20518653. S2CID   24874530.
  30. ↑ Singh VK, Beattie LA, Seed TM (November 2013). "Vitamin E: tocopherols and tocotrienols as potential radiation countermeasures". Journal of Radiation Research. 54 (6): 973–88. doi:10.1093/jrr/rrt048. PMC   3823775 . PMID   23658414.
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