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

Tocotrienols are plant-derived natural products belonging to the vitamin E family of diterpenoids. They exist as four isomers (alpha, beta, gamma, delta), each differing in the number and position of methyl groups on their chromanol ring. Tocotrienols are distinguished from the closely related tocopherols by their side chains: tocotrienols have three unsaturated isoprenoid double bonds, whereas tocopherols have a fully saturated side chain. [1] [2]

Contents

Tocotrienols are compounds naturally occurring in some foods sources, the richest being palm oil, but to a lesser extent rice bran oil, barley, oats, and certain 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.

Medical applications

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]

Disease biomarkers

Reviews of human research linked tocotrienol threatment to improved biomarkers for inflammation and cardiovascular disease, although those did not report any information on clinically significant disease outcomes. [10] [11] Biomarkers for other diseases were not affected by tocotrienol supplementation. [12]

History

The discovery of tocotrienols was first reported by Pennock and Whittle in 1964, describing the isolation of tocotrienols from rubber. [13] 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. [14] During the 1990s, the anti-cancer properties of tocopherols and tocotrienols began to be delineated. [15] The current commercial sources of tocotrienol are rice bran oil and palm oil. [4] Other natural tocotrienol sources include barley and oats. [4] Tocotrienols are safe and human studies show no adverse effects with consumption of 240 mg/day for 48 months. [16]

The discovery of vitamin E by scientists Katherine Bishop and Herbert Evans in 1922 marked the beginning of the understanding of tocotrienols. [17] Vitamin E was named "tocopherol" (from the Greek words tokos, meaning childbirth, and phero, meaning to bring forth) due to its presumed role in aiding conception.

Subsequent research identified eight molecules in the vitamin E family, divided into tocopherols and tocotrienols: alpha, beta, delta, and gamma forms. [18] While tocotrienols were discovered later in the 1960s, researchers initially focused on tocopherols, particularly alpha-tocopherol, believed to be the most biologically active form of vitamin E. [19]

It was not until the late 1980s and early 1990s that tocotrienols began receiving more scientific attention. The term "tocotrienol" was introduced by Dr. Banyan to distinguish this isomer of vitamin E. [20]

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 ]

Research suggests tocotrienols are better antioxidants than tocopherols. [21] [22] [23] [24] It has been proposed that the unsaturated side-chain in tocotrienols causes them to penetrate tissues with saturated fatty layers more efficiently than tocopherol. [25] Lipid ORAC values are highest for δ-tocotrienol. 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." [26]

Metabolism and bioavailability

Absorption and distribution

As dietary supplements, 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. [27]

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%. [27]

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. [27]

Sources

In nature, tocotrienols are present in many fruits and vegetables. [28] 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.

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">Lycopene</span> Carotenoid pigment

Lycopene is an organic compound classified as a tetraterpene and a carotene. Lycopene is a bright red carotenoid hydrocarbon found in tomatoes and other red fruits and vegetables.

<span class="mw-page-title-main">Vitamin C</span> Essential nutrient found in citrus fruits and other foods

Vitamin C is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription dietary supplement. As a therapy, it is used to prevent and treat scurvy, a disease caused by vitamin C deficiency.

<span class="mw-page-title-main">Vitamin</span> Nutrients required by organisms in small amounts

Vitamins are organic molecules that are essential to an organism in small quantities for proper metabolic function. Essential nutrients cannot be synthesized in the organism in sufficient quantities for survival, and therefore must be obtained through the diet. For example, vitamin C can be synthesized by some species but not by others; it is not considered a vitamin in the first instance but is in the second. Most vitamins are not single molecules, but groups of related molecules called vitamers. For example, there are eight vitamers of vitamin E: four tocopherols and four tocotrienols.

Vitamin E is a group of eight compounds related in molecular structure that includes four tocopherols and four tocotrienols. The tocopherols function as fat-soluble antioxidants which may help protect cell membranes from reactive oxygen species. Vitamin E is classified as an essential nutrient for humans. Various government organizations recommend that adults consume between 3 and 15 mg per day, while a 2016 worldwide review reported a median dietary intake of 6.2 mg per day. Sources rich in vitamin E include seeds, nuts, seed oils, peanut butter, vitamin E–fortified foods, and dietary supplements. Symptomatic vitamin E deficiency is rare, usually caused by an underlying problem with digesting dietary fat rather than from a diet low in vitamin E. Deficiency can cause neurological disorders.

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.

A nutrient is a substance used by an organism to survive, grow and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi and protists. Nutrients can be incorporated into cells for metabolic purposes or excreted by cells to create non-cellular structures such as hair, scales, feathers, or exoskeletons. Some nutrients can be metabolically converted into smaller molecules in the process of releasing energy such as for carbohydrates, lipids, proteins and fermentation products leading to end-products of water and carbon dioxide. All organisms require water. Essential nutrients for animals are the energy sources, some of the amino acids that are combined to create proteins, a subset of fatty acids, vitamins and certain minerals. Plants require more diverse minerals absorbed through roots, plus carbon dioxide and oxygen absorbed through leaves. Fungi live on dead or living organic matter and meet nutrient needs from their host.

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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">Stanol ester</span> Class of chemical compounds

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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, along with an aromatic ring is situated near the carbonyls in the fatty acyl chains of the phospholipid bilayer, allows for penetration into biological membranes. It is found most in the membrane's non-raft domains, associated with omega-3 and 6 fatty acids, to partially prevent oxidation. The most prevalent form, α-tocopherol, is involved in molecular, cellular, biochemical processes closely related to overall lipoprotein and lipid homeostasis. Compared to the others, α-tocopherol is preferentially absorbed and accumulated in humans.

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

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

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

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References

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  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.
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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.
  8. ↑ Dietary Reference Intakes (DRIs): Recommended Intakes for Individuals (Report). Food and Nutrition Board, Institute of Medicine, National Academies. 2004. Archived from the original on 2010-05-24. Retrieved 2009-06-09– via www.iom.edu.
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  12. ↑ Li F, Xu B, Soltanieh S, Zanghelini F, Abu-Zaid A, Sun J (2022). "The effects of tocotrienols intake on obesity, blood pressure, inflammation, liver and glucose biomarkers: a meta-analysis of randomized controlled trials". Crit Rev Food Sci Nutr. 62 (26): 7154–67. doi:10.1080/10408398.2021.1911926. PMID   33909529.
  13. ↑ 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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  17. ↑ Sen CK, Khanna S, Roy S (2007-10-01). "Tocotrienols in health and disease: the other half of the natural vitamin E family". Molecular Aspects of Medicine. Vitamin E: An Overview of Major Research Directions. 28 (5–6): 692–728. doi:10.1016/j.mam.2007.03.001. PMC   2435257 . PMID   17507086.
  18. ↑ Li F, Xu B, Soltanieh S, Zanghelini F, Abu-Zaid A, Sun J (2022-09-12). "The effects of tocotrienols intake on obesity, blood pressure, inflammation, liver and glucose biomarkers: a meta-analysis of randomized controlled trials". Critical Reviews in Food Science and Nutrition. 62 (26): 7154–7167. doi:10.1080/10408398.2021.1911926. PMID   33909529.
  19. ↑ Rafique S, Khan DA, Farhat K, Khan MA, Noor M, Sharif M (June 2024). "Comparative efficacy of tocotrienol and tocopherol (vitamin E) on atherosclerotic cardiovascular diseases in humans". JPMA. The Journal of the Pakistan Medical Association. 74 (6): 1124–1129. doi: 10.47391/JPMA.9227 . PMID   38948984.
  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): 731–742. doi:10.1002/mnfr.200900399. PMID   20333724.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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.
  27. 1 2 3 Sharif M, Khan DA, Farhat K, Noor M, Khan MA, Rafique S (March 2023). "Pharmacokinetics and bioavailability of tocotrienols in healthy human volunteers: a systematic review". JPMA. The Journal of the Pakistan Medical Association. 73 (3): 603–610. doi: 10.47391/JPMA.6008 . PMID   36932765. S2CID   257423183. Archived from the original on 2023-03-26.
  28. ↑ Chun J, Lee J, Ye L, Exler J, Eitenmiller RR (March 2006). "Tocopherol and tocotrienol contents of raw and processed fruits and vegetables in the United States diet" (PDF). Journal of Food Composition and Analysis. 19 (2–3): 196–204. doi:10.1016/j.jfca.2005.08.001.
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