Pharmacological Potential of Tocotrienols: A Review
Pharmacological Potential of Tocotrienols: A Review
To start with, quoting Paracelsus (1493–1541 Switzerland), "in all things there is a poison, and there is nothing without a poison. It depends on only upon the dose whether a poison is a poison or not". Under dietary considerations, tocotrienol has been regarded as a safe biomolecule and experimental studies have also supported this view. There is no possible report of any adverse reactions caused by tocotrienol, except that in a study done on experimental animals in a 13-week oral toxicity study performed in Fischer 344 rats of both sexes at dose levels of 0% (group 1), 0.19% (group 2), 0.75% (group 3) and 3% (group 4) of a diet preparation in powdered form. On hematological examination, significant decrease in mean corpuscular volume (MCV) was observed in all treated males. Platelets were significantly reduced in group 3 and 4 males. Hemoglobin concentration, MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration were significantly decreased in group 3 and 4 females and hematocrit in group 4 females. On biochemical examination, increase in the albumin/globulin ratio (A/G) and alkaline phosphatase in all treated males, elevated alanine transaminase in group 4 of both sexes and increases in asparagine transaminase and gamma-glutamyl transaminase in group 4 females were observed. With regard to relative organ weights, liver weights in group 4 of both sexes and adrenal weights in all treated males demonstrated an increase, and ovary and uterus weights in group 4 females were reduced. A slight hepatocellular hypertrophy in group 3 and 4 males, and reduction of cytoplasmic vacuolation in the adrenal cortical region in group 4 males were observed. Because of pathological changes in male liver and hematological changes in females, the no-observed-adverse-effect level (NOAEL) was concluded to be 0.19% in the diet (120 mg/kg for male rats and 130 mg/kg body weight/day for female rats). Since, most of the studies have been in favor of tocotrienols, however, it needs to be replicated in human populations to evaluate the safety and efficacy of tocotrienols as a therapeutic agent or drug.
There are convincing evidence that tocotrienols are detectable at appreciable levels in the plasma after short term and long term supplementations. However, there is insufficient data on the range of plasma concentrations of tocotrienols that are adequate to demonstrate significant physiological effects. Although the pharmacokinetics of tocotrienols are distinctly different from tocopherols which are well studied and remained longer in blood circulation, biodistribution study showed considerable accumulation of tocotrienols in vital organs. In the perspective of therapeutic efficacy, it is evident that the outcome of clinical evaluations is not only affected by the bioavailability of tocotrienols. In view of the limited understanding, more studies on the mechanisms of absorption are essential.
In an effort to determine the therapeutic window for tocotrienols, a number of long term clinical studies have been carried out using TRF and tocotrienol derivatives. The majority of these trials were focused on lipid profile as tocotrienols were found to inhibit HMG-CoA reductase. However, the optimum dosing regimen to induce therapeutic effects remained unclear.
Although most studies were conducted in rodents and animals, they serve as a basis for clinical evaluations to establish their health benefits in humans. A number of clinical trials were conducted to examine the multi-faceted health benefits of tocotrienols in different populations. The bioavailability and efficacy of TRF may vary in different populations. tocotrienols seem to respond differently to a range of age groups but did not show consistent efficacies in the target study populations. Most of the studies conducted in patients with chronic diseases had relatively small sample size. This demonstrates the need to conduct randomized controlled trials in larger population to confidently evaluate the therapeutic potentials of tocotrienols.
Patel et al. have determined the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg a-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Skin and serum vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. The vitamin E levels in vital organ were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1–96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. a-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. The finding of the study is the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans. Their work provides the first evidence on tissue availability of TE in vital organs of adult humans following oral supplementation to characterize multiple vital organ concentration of TCP in adults. TE was delivered and accumulated in vital human organs supports future studies to identify specific mechanisms of tissue delivery and metabolism. The outcomes of this work provide clear evidence that oral TE supplementation enriches its concentration in whole blood, adipose, skin, brain, cardiac muscle, and liver.
Toxicity and Dosage
To start with, quoting Paracelsus (1493–1541 Switzerland), "in all things there is a poison, and there is nothing without a poison. It depends on only upon the dose whether a poison is a poison or not". Under dietary considerations, tocotrienol has been regarded as a safe biomolecule and experimental studies have also supported this view. There is no possible report of any adverse reactions caused by tocotrienol, except that in a study done on experimental animals in a 13-week oral toxicity study performed in Fischer 344 rats of both sexes at dose levels of 0% (group 1), 0.19% (group 2), 0.75% (group 3) and 3% (group 4) of a diet preparation in powdered form. On hematological examination, significant decrease in mean corpuscular volume (MCV) was observed in all treated males. Platelets were significantly reduced in group 3 and 4 males. Hemoglobin concentration, MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration were significantly decreased in group 3 and 4 females and hematocrit in group 4 females. On biochemical examination, increase in the albumin/globulin ratio (A/G) and alkaline phosphatase in all treated males, elevated alanine transaminase in group 4 of both sexes and increases in asparagine transaminase and gamma-glutamyl transaminase in group 4 females were observed. With regard to relative organ weights, liver weights in group 4 of both sexes and adrenal weights in all treated males demonstrated an increase, and ovary and uterus weights in group 4 females were reduced. A slight hepatocellular hypertrophy in group 3 and 4 males, and reduction of cytoplasmic vacuolation in the adrenal cortical region in group 4 males were observed. Because of pathological changes in male liver and hematological changes in females, the no-observed-adverse-effect level (NOAEL) was concluded to be 0.19% in the diet (120 mg/kg for male rats and 130 mg/kg body weight/day for female rats). Since, most of the studies have been in favor of tocotrienols, however, it needs to be replicated in human populations to evaluate the safety and efficacy of tocotrienols as a therapeutic agent or drug.
There are convincing evidence that tocotrienols are detectable at appreciable levels in the plasma after short term and long term supplementations. However, there is insufficient data on the range of plasma concentrations of tocotrienols that are adequate to demonstrate significant physiological effects. Although the pharmacokinetics of tocotrienols are distinctly different from tocopherols which are well studied and remained longer in blood circulation, biodistribution study showed considerable accumulation of tocotrienols in vital organs. In the perspective of therapeutic efficacy, it is evident that the outcome of clinical evaluations is not only affected by the bioavailability of tocotrienols. In view of the limited understanding, more studies on the mechanisms of absorption are essential.
In an effort to determine the therapeutic window for tocotrienols, a number of long term clinical studies have been carried out using TRF and tocotrienol derivatives. The majority of these trials were focused on lipid profile as tocotrienols were found to inhibit HMG-CoA reductase. However, the optimum dosing regimen to induce therapeutic effects remained unclear.
Although most studies were conducted in rodents and animals, they serve as a basis for clinical evaluations to establish their health benefits in humans. A number of clinical trials were conducted to examine the multi-faceted health benefits of tocotrienols in different populations. The bioavailability and efficacy of TRF may vary in different populations. tocotrienols seem to respond differently to a range of age groups but did not show consistent efficacies in the target study populations. Most of the studies conducted in patients with chronic diseases had relatively small sample size. This demonstrates the need to conduct randomized controlled trials in larger population to confidently evaluate the therapeutic potentials of tocotrienols.
Patel et al. have determined the concentrations of TE (200 mg mixed TE, b.i.d.) and TCP [200 mg a-TCP, b.i.d.)] in vital tissues and organs of adults receiving oral supplementation. Skin and serum vitamin E concentrations were determined from healthy participants following 12 wk of oral supplementation of TE or TCP. The vitamin E levels in vital organ were determined by HPLC in adipose, brain, cardiac muscle, and liver of surgical patients following oral TE or TCP supplementation (mean duration, 20 wk; range, 1–96 wk). Oral supplementation of TE significantly increased the TE tissue concentrations in blood, skin, adipose, brain, cardiac muscle, and liver over time. a-TE was delivered to human brain at a concentration reported to be neuroprotective in experimental models of stroke. The finding of the study is the foundation for Phase II clinical trials testing the efficacy of TE against stroke and end-stage liver disease in humans. Their work provides the first evidence on tissue availability of TE in vital organs of adult humans following oral supplementation to characterize multiple vital organ concentration of TCP in adults. TE was delivered and accumulated in vital human organs supports future studies to identify specific mechanisms of tissue delivery and metabolism. The outcomes of this work provide clear evidence that oral TE supplementation enriches its concentration in whole blood, adipose, skin, brain, cardiac muscle, and liver.
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