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Influence of route of administration on the absorption and disposition of alpha-, gamma- and delta-tocotrienols in rats

Yap SP, Yuen KH, Lim AB

J Pharm Pharmacol, 2003 Jan;55(1):53-8.
PMID: 12625867

A study was conducted to evaluate the bioavailability of alpha-, gamma- and delta-tocotrienols administered via oral, intravenous, intramuscular and intraperitoneal routes in rats. Three separate experiments, each conducted according to a two-way crossover design, were carried out to compare intravenous and oral, intramuscular and oral, and intraperitoneal and oral administration. Oral absorption of all three tocotrienols was found to be incomplete. Of the three tocotrienols, alpha-tocotrienol had the highest oral bioavailability, at about 27.7+/-9.2%, compared with gamma- and delta-tocotrienols, which had values of 9.1+/-2.4% and 8.5+/-3.5%, respectively. Such biodiscrimination was also observed in their total clearance rates (estimated from the intravenous data). alpha-Tocotrienol showed the lowest clearance rate at about 0.16 L kg(-1) h(-1), whereas that of delta- and gamma-tocotrienols was quite similar, with values of 0.24 and 0.23 L kg(-1) h(-1), respectively. Interestingly, all three tocotrienols were found to be negligibly absorbed when administered intraperitoneally and intramuscularly. Thus, these two routes of administration should be avoided when evaluating the biological activities of the tocotrienols in whole animal experiments.

Matched MeSH terms: Chromans/administration & dosage*
Fulltext Gamma-tocotrienol and hydroxy-chavicol synergistically inhibits growth and induces apoptosis of human glioma cells

Abdul Rahman A, Jamal AR, Harun R, Mohd Mokhtar N, Wan Ngah WZ

BMC Complement Altern Med, 2014;14:213.
PMID: 24980711 DOI: 10.1186/1472-6882-14-213

Gamma-tocotrienol (GTT), an isomer of vitamin E and hydroxy-chavicol (HC), a major bioactive compound in Piper betle, has been reported to possess anti-carcinogenic properties by modulating different cellular signaling events. One possible strategy to overcome multi-drug resistance and high toxic doses of treatment is by applying combinational therapy especially using natural bioactives in cancer treatment.

Matched MeSH terms: Chromans/administration & dosage
Different starting times of alpha-tocopherol and gamma-tocotrienol supplementation and tumor marker enzyme activities in the rat chemically induced with cancer

Makpol S, Shamaan NA, Jarien Z, Top AG, Khalid BA, Wan Ngah WZ

Gen. Pharmacol., 1997 Apr;28(4):589-92.
PMID: 9147029

1. alpha-Tocopherol (alpha-T) and gamma-tocotrienol (gamma-T) were supplemented continuously for 8 weeks in the diets of normal rats and rats chemically induced with cancer using diethylnitrosamine (DEN), 2-acetylaminofluorene (AAF) and partial hepatectomy. Hepatocarcinogenesis was followed by determining the plasma gamma-glutamyl-transpeptidase (GGT) and alkaline phosphatase (ALP) activities as well as placental glutathione S-transferase (PGST) and GGT activities histochemically, at 4-week intervals. 2. Male Rattus norvegicus were supplemented alpha-T and gamma-T at two different doses of 30 and 300 mg/kg diet. The supplementation was started at three different times: simultaneously with DEN administration; 4 weeks; and 8 weeks after DEN administration. 3. Elevation of plasma GGT activities and formation of PGST and GGT positive foci were attenuated significantly (P < 0.05) when alpha-T and gamma-T were supplemented simultaneously with cancer induction. Supplementation begun 4 and 8 weeks after cancer induction did not affect plasma enzyme activities and formation of enzyme-positive foci. 4. alpha-T was more effective than gamma-T, and a lower dose of 30 mg/kg was found to be more effective in reducing the severity of hepatocarcinogenesis.

Matched MeSH terms: Chromans/administration & dosage*
Comparing palm oil tocotrienol rich fraction with α-tocopherol supplementation on oxidative stress in healthy older adults

Goon JA, Nor Azman NHE, Abdul Ghani SM, Hamid Z, Wan Ngah WZ

Clin Nutr ESPEN, 2017 10;21:1-12.
PMID: 30014863 DOI: 10.1016/j.clnesp.2017.07.004

Vitamin E is a fat-soluble compound and powerful antioxidant that have been shown to protect the cell membranes against damage caused by free radicals. Human vitamin E supplementation studies are usually limited to α-tocopherol but currently tocotrienols are also available. This study aims to compare the effects of tocotrienol rich fraction (TRF) with α-tocopherol (α-TF) supplementation on oxidative stress in healthy male and female older adults aged 50-55 years old. A total of 71 subjects both male and female aged between 50 and 55 years were divided into groups receiving placebo (n = 23), α-TF (n = 24) and TRF (n = 24) for six months. Blood was taken at baseline (month 0), 3 months and 6 months osf supplementation for determination of plasma malondialdehyde (MDA), protein carbonyl, total DNA damage, vitamin D concentration and vitamin E isomers. α-TF supplementation reduced plasma MDA and protein carbonyl in female subjects after 3 and 6 months. TRF supplementation reduced MDA levels in both males and females as early as 3 months while DNA damage was reduced in females only at 6 months. Supplementation with α-TF and TRF increased plasma vitamin D concentration in both males and females after 6 months, but vitamin D concentration in male subjects were significantly higher compared to female subjects in TRF group. Vitamin E isomer determination showed α-TF, α-tocotrienol and γ-tocotrienol were increased in both male and female subjects. In conclusion, TRF supplementation effects were different from α-TF in reducing oxidative stress markers and vitamin D levels with a more pronounced effect in female subjects.

Matched MeSH terms: Chromans/administration & dosage*
Vitamin E exhibits bone anabolic actions in normal male rats

Shuid AN, Mehat Z, Mohamed N, Muhammad N, Soelaiman IN

J. Bone Miner. Metab., 2010 Mar;28(2):149-56.
PMID: 19779668 DOI: 10.1007/s00774-009-0122-2

Recently, vitamin E has been found to promote the bone structure of nicotine-treated rats well above their baseline values, thus suggesting that vitamin E may have some anabolic action. A bone anabolic agent acts by improving the bone structure leading to stronger bone. To assess the possible anabolic action vitamin E on bone, we supplemented alpha-tocopherol (ATF) or gamma-tocotrienol (GTT) at 60 mg/kg or vehicle [normal control (NC) group] for 4 months to normal male rats and measured their bone structure and biomechanical properties. Histomorphometric analysis revealed that vitamin E-supplemented rats have better trabecular volume, thickness, number, and separation than rats receiving vehicle only. For the first time we reported that GTT improves all the parameters of bone biomechanical strength, while ATF only improved some of the parameters compared to the NC group. Vitamin E supplementation, especially with the gamma isomer, improves bone structure, which contributed to stronger bone. Therefore, vitamin E has the potential to be used as an anabolic agent to treat osteoporosis or as bone supplements for young adults to prevent osteoporosis in later years.

Matched MeSH terms: Chromans/administration & dosage
Enhancement of apoptotic activities on brain cancer cells via the combination of γ-tocotrienol and jerantinine A

Abubakar IB, Lim KH, Kam TS, Loh HS

Phytomedicine, 2017 Jul 01;30:74-84.
PMID: 28545672 DOI: 10.1016/j.phymed.2017.03.004

BACKGROUND: γ-Tocotrienol, a vitamin E isomer possesses pronounced in vitro anticancer activities. However, the in vivo potency has been limited by hardly achievable therapeutic levels owing to inefficient high-dose oral delivery which leads to subsequent metabolic degradation. Jerantinine A, an Aspidosperma alkaloid, originally isolated from Tabernaemontana corymbosa, has proved to possess interesting anticancer activities. However, jerantinine A also induces toxicity to non-cancerous cells.
PURPOSE: We adopted a combinatorial approach with the joint application of γ-tocotrienol and jerantinine A at lower concentrations in order to minimize toxicity towards non-cancerous cells while improving the potency on brain cancer cells.
METHODS: The antiproliferative potency of individual γ-tocotrienol and jerantinine A as well as combined in low-concentration was firstly evaluated on U87MG cancer and MRC5 normal cells. Morphological changes, DNA damage patterns, cell cycle arrests and the effects of individual and combined low-concentration compounds on microtubules were then investigated. Finally, the potential roles of caspase enzymes and apoptosis-related proteins in mediating the apoptotic mechanisms were investigated using apoptosis antibody array, ELISA and Western blotting analysis.
RESULTS: Combinatorial study between γ-tocotrienol at a concentration range (0-24µg/ml) and fixed IC20 concentration of jerantinine A (0.16µg/ml) induced a potent antiproliferative effect on U87MG cells and led to a reduction on the new half maximal inhibitory concentration of γ-tocotrienol (i.e.tIC50=1.29µg/ml) as compared to that of individual γ-tocotrienol (i.e. IC50=3.17µg/ml). A reduction on undesirable toxicity to MRC5 normal cells was also observed. G0/G1 cell cycle arrest was evident on U87MG cells receiving IC50 of individual γ-tocotrienol and combined low-concentration compounds (1.29µg/ml γ-tocotrienol + 0.16µg/ml jerantinine A), whereas, a profound G2/M arrest was evident on cells treated with IC50 of individual jerantinine A. Additionally, individual jerantinine A and combined compounds (except individual γ-tocotrienol) caused a disruption of microtubule networks triggering Fas- and p53-induced apoptosis mediated via the death receptor and mitochondrial pathways.
CONCLUSIONS: These findings demonstrated that the combined use of lower concentrations of γ-tocotrienol and jerantinine A induced potent cytotoxic effects on U87MG cancer cells resulting in a reduction on the required individual concentrations and thereby minimizing toxicity of jerantinine A towards non-cancerous MRC5 cells as well as probably overcoming the high-dose limiting application of γ-tocotrienol. The multi-targeted mechanisms of action of the combination approach have shown a therapeutic potential against brain cancer in vitro and therefore, further in vivo investigations using a suitable animal model should be the way forward.

Matched MeSH terms: Chromans/administration & dosage
Deleterious effects of nicotine on the ultrastructure of oocytes: role of gamma-tocotrienol

Rajikin MH, Latif ES, Mar MR, Mat Top AG, Mokhtar NM

Med Sci Monit, 2009 Dec;15(12):BR378-83.
PMID: 19946227

Previous studies have shown that nicotine enhances oxidative DNA damage and leads to increased lipid peroxidation, which affects embryo development. The present study investigated the effect of daily supplementation of gamma-tocotrienol on oocytes of nicotine-treated mice.

Matched MeSH terms: Chromans/administration & dosage