Radiation damage is an annoying side effect of radiation therapy causing the so-called endothelial dysfunction, which often results in tissues damage.

Radiotherapy may cause damage to the cells of the vascular endothelium (endothelial cells), since oxidative stress is increased by radiation.
But not only radiation causes of oxidative stress.

Even in everyday life, human beings are exposed to oxidative stress, which can lead to vascular or tissue damage. Thus this study is important for radiotherapy patients as well as for those people who are exposed to increased oxidative stress.

Oxidative stress may imbalance the vascular relaxing enzyme NO synthase. Under these conditions, the so-called uncoupling occurs more frequently. In healthy individuals, the enzyme NO synthase is coupled and thus provides the important nitric oxide. Nitric oxide (NO) is essential for vascular health and healthy blood pressure. In the event of uncoupling, the cytotoxic radicals such as superoxide and peroxynitrite are increasingly formed instead of the important nitric oxide.

NO synthases do not only fulfill a central role in the vessels, but also in the whole body (e.g. in pathogen defense, nerve health, regulation of programmed cell death, etc.).

The essential end product for the body is ultimately the small and volatile nitric oxide molecule formed by the NO synthases.

Oxidation of BH4 into BH2 through radiation exposure results in uncoupling of NO synthase and vascular damage. Subsequently, tissue damage often occurs.

A coupled condition of NO synthases is dependent on an adequate amount of BH4. Oxidation of BH4 through radicals reduces BH4 in favor of BH2. BH2 promotes uncoupling. The uncoupling of NO synthases will inevitably lead to an increased formation of the extremely harmful cell and tissue-toxic radicals such as superoxide and peroxynitrite.

Vitamin E (gamma-tocotrienol) protects blood vessels and tissues from radiation damage by preventing the oxidation of BH4.

Scientists assume that the positive effect of BH4 (tetrahydrobiopterin) concentrations represents a realistic possibility to reduce vascular and tissue damage after radiation therapy in humans [1].
With a high-dosage of gamma-tocotrienols (400 mg / kg), radiation damage and the resultant mortality were greatly reduced in animals [2] [3].
Vascular damage and tissue damage of the gastrointestinal tract were reduced and the recovery of the hematopoietic system after radiation was promoted.

Delta and gamma tocotrienols inhibit the activity of the enzyme HMG-CoA reductase in animals and humans [4] [5]. The de novo synthesis of BH4 is thus promoted.

The inhibition of the enzyme HMG-CoA reductase was aspired mainly because of the inhibitory effect on cholesterol synthesis. However, the positive effect on the coupling status of NO synthase by promoting BH4 regeneration rate is another very important effect.

In order to achieve an inhibition of the enzyme HMG-CoA reductase, statins (cholesterol-lowering agents) are used in conventional medicine. These have the effect that the Q10 levels in the body are reduced.
CoQ10 is essential for cellular respiration in the “power plants” of the cell. An unwanted and dreaded side effect of statins is the triggered muscle pain [6].
Statins inhibit the formation of mevalonic acid, which is needed for the formation of cholesterol. However, since mevalonic acid is also a precursor of the coenzyme Q10, a reduction in the Q10 levels in the body occurs. Tocotrienols and tocopherols stimulate the degradation of the HMG-CoA reductase. Statins inhibit the enzyme competitively.

Q10 depletion through tocotrienols has in contrast to the known Q10 depletion by statins not yet been described [6].

Radiation exposure leads to uncoupling of NO synthase and increased peroxynitrite formation. Vitamin E (gamma-tocopherol) intercepts the highly toxic peroxynitrite and hinders its formation by preventing uncoupling [7] [8].

The important BH4 for the NO synthase is increasingly oxidized through peroxynitrite, which exactly like in radiation damage leads again to uncoupling. The uncoupled enzyme supplies superoxide instead of nitric oxide (NO). Superoxide is able to react with the available nitric oxide (NO) and form peroxynitrite.
Thus, the fatal vicious circle is closed. Tocotrienols and tocopherols (vitamin E) are capable of precisely breaking this vicious circle.

[1] Novel Strategies to Ameliorate Radiation Injury: A Possible Role for Tetrahydrobiopterin (BH4)
[2] Gamma-Tocotrienol Ameliorates Gastrointestinal and Vascular Radiation Injury
[3] Gamma-Tocotrienol, a Tocol Antioxidant and a Potent Radiation Protector
[4] Tocotrienols Regulate Cholesterol Production in Mammalian Cells by Post-Transcriptional Suppression of HMG-CoA Reductase
[5] Delta- and Gamma-Tocotrienols Stimulate the Degradation of HMG-CoA Reductase
[6] Coenzyme Q10 and Statin-Induced Mitochondrial Dysfunction
[7] Gamma-Tocopherol is a Physiological Peroxinitrite Scavenger
[8] Vitamin E Inhibits the Formation of Peroxinitrite