Tocols As Radiation Countermeasures

Navita Bansal, Vinutha T, Khushboo Kumari, Shelly Praveen Division of Biochemistry, IARI

2019-01-23 10:24:43

Figure 1

Figure 1

Tocopherols and tocotrienols collectively known as vitamin E (vit-E) or tocols are important dietery nutrient because of their remarkable biological activities including antioxidant activity, neuroprotective and anti-inflammatory properties. The daily requirement for vit-E is 15mg for an adult and can be obtained naturally from nuts (almonds, peanuts and hazelnuts and  oils mainly soybean, safflower and wheatgerm oil  or  from vit-E fortified diets. (source: U.S. National Library of Medicine). Vit-E was first discovered in 1922 by Bishop and Evans, isolated in 1935 and first synthesized in 1938.

Vit- E was named as tocopherol - a Greek word which means birth or to carry as its activity was first time found essential for the fertilized eggs  in live births in rats. Vit- E has been shown to be very effective against cellular oxidative damage that has been linked to the basis of various diseases and disorders, including cancer, ageing, arthritis and cataracts. Apart from the significant role  of natural vit- E in various biological processess, tocols are also well recognized for their significant role as radiation countermeasures not only by scavenging free radicals generated through irradiation, but also through inducing high levels of  cytokines and chemokines (Cytokines/chemokines are cell signalling molecules which play vital role in various  immune responses in our body) and by suppressing chronic radiation- induced fibrosis in some organ systems. Considering the extensive use of ionizing radiation in various clinical and non-clinical fields which include diagnostic purposes (exposure to X-ray,various diagnostic machines and instruments), cancer treatment, radiations generated through nuclear energy production, engineering and construction (building materials like sandstone,concrete,gypsum, granite etc release low levels of radiations as they contain naturally occurring radioactive elements like uranium,thorium and radium), and sterilization of food products by γ rays mainly has promoted for identification, developement and investigating the effective and promising radiation countermeasures. An effective radiation countermeasures should be safe, stable, easy to administer, and have good bioavailability.

Exposure to ionizing radiation generates free radicals including hydroxyl radical (OH•), superoxide (O2), peroxynitrite (ONOO), and hydrogen peroxide (H2O2) which damage DNA, proteins, and lipids as well as stimulate release of cytochrome C from mitochondria.( key protein involved in apoptotic pathway), leading to programmed cell death. ROS damages DNA by modifying bases, formation of inter and intra strand crosslinks and DNA-protein crooslinks  that leads to lesion formation which induces mutagenesis and normal processes of DNA replication and transcription are affected (Fig 1).  Till date, amifostine is the only FDA approved drug used for patients undergoing radiotherapy but it has many adverse side effects associated with it and hence the search for safe and effective radiation countermeasures is a matter of great concern. Exposure to ionizing radiation with doses higher than 1 Gray (Gy) for a brief period can cause severe tissue injuries, referred to as Acute Radiation Syndrome (ARS) and is mainly categorized under three distinct subsyndromes (1) Hematopoeitic (2) gastrointenstinal(GI) and (3) neuro/cerebrovascular depending upon radiation exposure to total dose, rate of dosage , duration and sensitivity of organs. Various  compounds such as polyphenols, thiols and superoxide dismutase mimetics have been used as potential radiation countermeasures in the past  but tocols and its derivatives mainly AT (α-tocopherol), DT3(δ-tocotrienol), GT3(γ-tocotrienol) and TS (α-tocopherol succinate) are also proving to be very effective against radiation exposure as they have minimal gastrointenstinal toxicity .

 Radiation countermeasures are classified into three categories viz. radioprotectors, mitigators and therapeutics. Radioprotectors are administerd before exposure to radiation, mitigators are given shortly after radiation exposure to and therapeutics are administered after symptoms start appearing.

Several studies have demonstrated the role of tocols as radioprotectors against radiation exposure when administerd subcutaneously 24h before radiation exposure. Reports showed that subcutaneous administration of AT when exposed  to 0.2 Gy/min irradiation increased the 30 day survival of mice. Tocotrienols are considered as better radio-protectants than tocopherols due to their ability to  efficiently interact with the lipid bilayer, also they are more uniformly  distributed within the lipid bilayers .Cellular uptake of α tocotrienol is about 70 times higher than AT. DT3 and GT3 are also very effective radiation countermeasures. It aws also found that a single injection of DT3, given to mice 24 h before a total body irradiation, showed 100% survival upto30-day post-irradiation, by increasing cell survival and regeneration of hematopoietic microfoci. Studies have shown that a single subcutaneous administration of GT3 prior to whole body irradiation can lower the  radiation injury in several organ systems, including the GI, the hematopoietic system and the vascular system. Tocotrienols are more efficient in reducing GI injury than tocopherols as they accumulate in the small intestine and in the colon to a greater level than tocopherols. Also, concentrations of GT3 in endothelial cells were 30–50 times greater than those of α-tocopherol. Also, GT3 has greater potency to induce gene expression in human endothelial cells than tocopherols and hence is more effective radioprotectants.

Tocols also found to be quite effective as radiotherapeutics and radiomitigators. TS (α-tocopherol succinate) which is a tocopherol derivative of AT without being affecting the normal cells, it enhanced radiation induced chromosomal damage in cancer cells. TS was shown to protect the intestinal tissue of irradiated mice with 60Co gamma rays through promoting the regeneration of crypt cells of small intenstine and inhibiting the apoptosis.Mechanism may include the stabilization of cytoplasmic membrane gut epithelia and enhancing cell proliferation. (fig 2).

TS was also shown to stimulate immune system through higher production cytokines mainly G-CSF (granulocyte-colony stimulating factor) and keratinocyte – derived chemokine (KC) in peripheral blood. DT3 reduces radiation induced cytopenia (reduction in the number of mature blood cells) through reduction of specific caspases involved in apoptotic pathway. DT3 protected mouse bone marrow and human CD34 cells ( found in umbilical cord and bone marrow as hematopoietic cells) from radiation damage through activation of various kinases of mTOR survival pathway.(fig3). The protective effects of GT3 in nonhuman primates treated with various   doses of cobalt-60 gamma radiation (0.6 Gy/min) had also evaluated. GT3 protects against radiation injury by increasing hematopoietic progenitors, neutrophils, platelets, white blood cells, and reticulocytes and was shown to decrease vascular oxidative stress.. GT3 accelerated hematopoetic recovery in irradiated mice by  inducing G-CSF and IL-6 (interleukin-6, a proinflammatory cytokine) within 12-24 hrs of its administration.  Considering  the  effectiveness and low toxicity, the tocols have proved to be effective to protect against low-dose radiation, however further research is required to establish their potential.