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Tocotrienol

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Not to be confused with the more common class of molecules that are also forms of vitamin E, the tocopherols.
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]

Alpha-Tocotrienol (α-Tocotrienol):

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  • Chemical Structure: Alpha-tocotrienol has three methyl groups at positions R1, R2, and R3 (R1 = Me, R2 = Me, R3 = Me).
  • Functions and Benefits:
    • Alpha-tocotrienol is known for its powerful antioxidant properties, protecting cells from oxidative stress and preventing lipid peroxidation (damage to fats in cell membranes).
    • It has been studied for its neuroprotective effects, especially in cases of stroke, where it can help reduce brain damage by protecting neurons.
    • Research shows alpha-tocotrienol may inhibit the production of harmful enzymes involved in brain cell death, providing a protective effect on neural tissues.
    • It also contributes to maintaining healthy skin and is known for its anti-inflammatory properties.
  • Sources: Common sources include rice bran oil, palm oil, and annatto.

2. Beta-Tocotrienol (β-Tocotrienol):

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  • Chemical Structure: Beta-tocotrienol has a methyl group at R1 and R3 but no methyl group at R2 (R1 = Me, R2 = H, R3 = Me).
  • Functions and Benefits:
    • Beta-tocotrienol is the least studied of the tocotrienols, but it still provides antioxidant protection, similar to the other members of the vitamin E family.
    • It contributes to lowering cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which is responsible for cholesterol synthesis in the liver.
  • Sources: Found in vegetable oils, rice bran oil, and barley.

3. Gamma-Tocotrienol (γ-Tocotrienol):

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  • Chemical Structure: Gamma-tocotrienol has a hydrogen at R1, a methyl group at R2, and a methyl group at R3 (R1 = H, R2 = Me, R3 = Me).
  • Functions and Benefits:
    • Gamma-tocotrienol is one of the most studied tocotrienols, especially for its potent anticancer effects. It has shown promise in inhibiting the growth of various cancer cells, including breast, colon, pancreatic, and prostate cancers.
    • It supports cardiovascular health by reducing cholesterol levels, primarily through its action on HMG-CoA reductase, similar to statins.
    • Additionally, gamma-tocotrienol helps protect the skin from UV damage and reduces oxidative stress in the body.
    • It also exhibits strong anti-inflammatory effects, which may benefit individuals with chronic inflammation-related conditions.
  • Sources: Found in high concentrations in palm oil, rice bran oil, and annatto.

4. Delta-Tocotrienol (δ-Tocotrienol):

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  • Chemical Structure: Delta-tocotrienol has no methyl group at R1 and R2, but has a methyl group at R3 (R1 = H, R2 = H, R3 = Me).
  • Functions and Benefits:
    • Delta-tocotrienol is considered the most potent tocotrienol in terms of antioxidant and anti-cancer properties. It has been extensively studied for its ability to inhibit cancer cell growth, particularly in pancreatic, breast, and prostate cancers.
    • It has been shown to induce apoptosis (programmed cell death) in cancer cells while sparing healthy cells.
    • Like other tocotrienols, delta-tocotrienol also supports cardiovascular health by lowering cholesterol and reducing inflammation.
    • Additionally, delta-tocotrienol has been linked to improved metabolic health, potentially helping in conditions like diabetes.
  • Sources: Annatto is one of the richest sources of delta-tocotrienol, along with palm oil and rice bran oil.

These variations in the placement of methyl (Me) and hydrogen (H) groups on the chromanol head structure determine their distinct properties and antioxidant activity. Among them, delta (δ)-tocotrienol and gamma (γ)-tocotrienol are considered the most potent in terms of health benefits, particularly due to their superior antioxidant and anti-inflammatory properties.

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

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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

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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

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Tocotrienols have been linked to improved markers of heart disease.[10] Tocotrienols have the potential to be used in patients undergoing angioplasty, stent implantation, and aorto-coronary bypass surgery. They are also effective in reducing ischemia-reperfusion cardiac injury in experimental animals and in lowering the risk of cardiac events in individuals with established ischemic heart disease.

Neuroprotection

Alpha-tocotrienol is known for its neuroprotective effects, especially in preventing neurodegeneration caused by oxidative stress. Studies suggest it could play a role in protecting the brain from stroke-related damage and other neurodegenerative diseases.

Skin and Hair Health

Due to their potent antioxidant capabilities, tocotrienols help protect skin and hair from environmental damage, reduce signs of aging, and promote skin repair.

Bone Health

Tocotrienols have been shown to prevent bone loss and support bone density, particularly in postmenopausal women.

History

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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

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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

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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

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Absorption and distribution

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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

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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

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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

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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

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Radiation countermeasures

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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

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  • Tan B, Watson RR, Preedy VR, eds. (2013). Tocotrienols: Vitamin E Beyond Tocopherols (2nd ed.). Boca Raton: CRC Press. ISBN 9781439884416.

References

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  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.
  5. ^ Cerecetto H, López GV (March 2007). "Antioxidants derived from vitamin E: an overview". Mini Reviews in Medicinal Chemistry. 7 (3): 315–38. doi:10.2174/138955707780059871. PMID 17346221.
  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.
  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.
  10. ^ Prasad K (2013). "Tocotrienols and cardiovascular health". Current Pharmaceutical Design. 17 (21): 825–834. doi:10.2174/138161211796957418. PMID 21774782.
  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.
  12. ^ Pearce BC, Parker RA, Deason ME, Qureshi AA, Wright JJ (October 1992). "Hypocholesterolemic activity of synthetic and natural tocotrienols". Journal of Medicinal Chemistry. 35 (20): 3595–606. doi:10.1021/jm00098a002. PMID 1433170.
  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
  15. ^ Packer L, Weber SU, Rimbach G (February 2001). "Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling". The Journal of Nutrition. 131 (2): 369S–73S. doi:10.1093/jn/131.2.369S. PMID 11160563.
  16. ^ Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML (December 1995). "Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis". Lipids. 30 (12): 1179–83. doi:10.1007/BF02536621. PMID 8614310. S2CID 4038103.
  17. ^ Serbinova E, Kagan V, Han D, Packer L (1991). "Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol". Free Radical Biology & Medicine. 10 (5): 263–75. doi:10.1016/0891-5849(91)90033-Y. PMID 1649783.
  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.
  19. ^ Wada S (2009). "Chemoprevention of tocotrienols: the mechanism of antiproliferative effects". Food Factors for Health Promotion. Forum of Nutrition. Vol. 61. pp. 204–16. doi:10.1159/000212752. ISBN 978-3-8055-9097-6. PMID 19367124.
  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. ^ a b c 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. ^ a b 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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