Tocotrienol Explained

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]

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]

Health effects

A number of health benefits of tocotrienols have been proposed, included decreased risk of heart disease and cancer. 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]

Skin

Tocotrienols have been linked to improve atopic eczema.[11]

Side effects

Tocotrienols are generally well tolerated and without significant side effects.[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 and palm.[16] Other natural tocotrienol sources include rice bran oil, coconut oil, cocoa butter, barley, and wheat germ.[17] Tocotrienols are safe and human studies show no adverse effects with consumption of 240 mg/day for 48 months.[18] 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.

Tocotrienol studies confirm anti-oxidation,[19] anti-inflammatory potentials and suggest anti-cancer effects[20] [21] better than the common forms of tocopherol due to their chemical structure. Scientists have suggested tocotrienols are better antioxidants than tocopherols.[22] [23] [24] [25] It has been proposed that the unsaturated side-chain in tocotrienols causes them to penetrate tissues with saturated fatty layers more efficiently than tocopherol.[26] Lipid ORAC values are highest for δ-tocotrienol.[27] 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.[28]

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%.[28]

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.[28]

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.[29]

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.[30] 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.[31] 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.[32] No human trials have yet been completed.

Further reading

External links

Notes and References

  1. Kamal-Eldin A, Appelqvist LA . The chemistry and antioxidant properties of tocopherols and tocotrienols . Lipids . 31 . 7 . 671–701 . July 1996 . 8827691 . 10.1007/BF02522884 . 4052785 . free .
  2. Clarke MW, Burnett JR, Croft KD . Vitamin E in human health and disease . Critical Reviews in Clinical Laboratory Sciences . 45 . 5 . 417–50 . 2008 . 18712629 . 10.1080/10408360802118625 . 85991655 .
  3. Book: Tan B, Watson RR, Preedy VR . Tocotrienols: Vitamin E Beyond Tocopherols . Boca Raton . CRC Press . 2013 . 2nd . 9781439884416.
  4. Sen CK, Rink C, Khanna S . 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 . June 2010 . 20823491 . 3065441 . 10.1080/07315724.2010.10719846 .
  5. Cerecetto H, López GV . Antioxidants derived from vitamin E: an overview . Mini Reviews in Medicinal Chemistry . 7 . 3 . 315–38 . March 2007 . 17346221 . 10.2174/138955707780059871 .
  6. Fu JY, Che HL, Tan DM, Teng KT . Bioavailability of tocotrienols: evidence in human studies . Nutrition & Metabolism . 11 . 1 . 5 . January 2014 . 24410975 . 3895660 . 10.1186/1743-7075-11-5 . free .
  7. Sen CK, Khanna S, Roy S . Tocotrienols in health and disease: the other half of the natural vitamin E family . Molecular Aspects of Medicine . 28 . 5–6 . 692–728 . 2007 . 17507086 . 2435257 . 10.1016/j.mam.2007.03.001 .
  8. Dietary Reference Intakes (DRIs): Recommended Intakes for Individuals. Food and Nutrition Board, Institute of Medicine, National Academies. 2004. https://web.archive.org/web/20100524031208/http://www.iom.edu/Global/News%20Announcements/~/media/Files/Activity%20Files/Nutrition/DRIs/DRISummaryListing2.ashx. 2010-05-24. dead. 2009-06-09. www.iom.edu.
  9. Georgousopoulou EN, Panagiotakos DB, Mellor DD, Naumovski N . Tocotrienols, health and ageing: A systematic review . Maturitas . 95 . 55–60 . January 2017 . 27889054 . 10.1016/j.maturitas.2016.11.003 .
  10. Prasad K . Tocotrienols and cardiovascular health . Current Pharmaceutical Design . 17 . 21 . 825–834 . 2013 . 21774782 . 10.2174/138161211796957418 .
  11. Tsuyoshi . Tsuduki . Keiko . Kuriyama . Kiyotaka . Nakagawa . Teruo . Miyazawa . Tocotrienol (Unsaturated Vitamin E) Suppresses Degranulation of Mast Cells and Reduces Allergic Dermatitis in Mice . Journal of Oleo Science . 62 . 10 . 2147–54 . 2011 . 24088520 . 10.5650/jos.62.825 . free .
  12. Meganathan P, Fu JY . Biological Properties of Tocotrienols: Evidence in Human Studies . International Journal of Molecular Sciences . 17 . 11 . 1682 . October 2016 . 27792171 . 5133770 . 10.3390/ijms17111682 . free .
  13. 10.1038/207521a0 . Identification and Estimation of Tocotrienols in Hevea Latex . 1965 . Dunphy . P. J. . Nature . 207 . 521–522 . Whittle . K. J. . Pennock . J. F. . Morton . R. A. . 4996. 1965Natur.207..521D . 4214464 .
  14. Pearce BC, Parker RA, Deason ME, Qureshi AA, Wright JJ . Hypocholesterolemic activity of synthetic and natural tocotrienols . Journal of Medicinal Chemistry . 35 . 20 . 3595–606 . October 1992 . 1433170 . 10.1021/jm00098a002 .
  15. Book: Schauss, Alexander G. . Tocotrienols: A Review . Watson . Ronald Ross . Preedy . Victor R. . 2008 . Tocotrienols: Vitamin E Beyond Tocopherols . CRC Press . 978-1-4200-8037-7 . 6.
  16. Tan, B. and M.H. Saleh, Integrated process for recovery of carotenoids and tocotrienols from oil in USPTO 5,157,132. 1992
  17. Packer L, Weber SU, Rimbach G . Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling . The Journal of Nutrition . 131 . 2 . 369S–73S . February 2001 . 11160563 . 10.1093/jn/131.2.369S . free .
  18. Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML . Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis . Lipids . 30 . 12 . 1179–83 . December 1995 . 8614310 . 10.1007/BF02536621 . 4038103 .
  19. Serbinova E, Kagan V, Han D, Packer L . Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol . Free Radical Biology & Medicine . 10 . 5 . 263–75 . 1991 . 1649783 . 10.1016/0891-5849(91)90033-Y .
  20. Constantinou C, Papas A, Constantinou AI . Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs . International Journal of Cancer . 123 . 4 . 739–52 . August 2008 . 18512238 . 10.1002/ijc.23689 . 3549712 . free .
  21. Book: Wada S . Food Factors for Health Promotion . Chemoprevention of tocotrienols: the mechanism of antiproliferative effects . 61 . 204–16 . 2009 . 19367124 . 10.1159/000212752 . Forum of Nutrition . 978-3-8055-9097-6.
  22. Müller L, Theile K, Böhm V . 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 . May 2010 . 20333724 . 10.1002/mnfr.200900399 .
  23. Yoshida Y, Niki E, Noguchi N . Comparative study on the action of tocopherols and tocotrienols as antioxidant: chemical and physical effects . Chemistry and Physics of Lipids . 123 . 1 . 63–75 . March 2003 . 12637165 . 10.1016/S0009-3084(02)00164-0 .
  24. Schaffer S, Müller WE, Eckert GP . Tocotrienols: constitutional effects in aging and disease . The Journal of Nutrition . 135 . 2 . 151–4 . February 2005 . 15671205 . 10.1093/jn/135.2.151 . free .
  25. Theriault A, Chao JT, Wang Q, Gapor A, Adeli K . Tocotrienol: a review of its therapeutic potential . Clinical Biochemistry . 32 . 5 . 309–19 . July 1999 . 10480444 . 10.1016/S0009-9120(99)00027-2 .
  26. Suzuki YJ, Tsuchiya M, Wassall SR, Choo YM, Govil G, Kagan VE, Packer L . 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 . October 1993 . 8399214 . 10.1021/bi00091a020 .
  27. Müller L, Theile K, Böhm V . 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 . May 2010 . 20333724 . 10.1002/mnfr.200900399 .
  28. Sharif . Mahjabeen . Khan . Dilshad Ahmed . Farhat . Kulsoom . 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 . 10.47391/JPMA.6008 . 0030-9982 . 36932765 . 257423183. free .
  29. https://www.ars.usda.gov/SP2UserFiles/Place/80400525/Articles/jfca19_196-204.pdf Tocopherol and tocotrienol contents of raw and processed fruits and vegetables in the United States diet
  30. Li XH, Fu D, Latif NH, Mullaney CP, Ney PH, Mog SR, Whitnall MH, Srinivasan V, Xiao M . 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 . December 2010 . 20823133 . 2995556 . 10.3324/haematol.2010.026492 .
  31. Kulkarni S, Ghosh SP, Satyamitra M, Mog S, Hieber K, Romanyukha L, Gambles K, Toles R, Kao TC, Hauer-Jensen M, Kumar KS . Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation . Radiation Research . 173 . 6 . 738–47 . June 2010 . 20518653 . 10.1667/RR1824.1 . 2010RadR..173..738K . 24874530 .
  32. Singh VK, Beattie LA, Seed TM . Vitamin E: tocopherols and tocotrienols as potential radiation countermeasures . Journal of Radiation Research . 54 . 6 . 973–88 . November 2013 . 23658414 . 3823775 . 10.1093/jrr/rrt048 .

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