There is constant low level background radiation from the cosmos but in certain situation the body may be subjected to increased acute or chronic exposure from other sources. This occurs in situations such as radiation accidents, medical use and could possibly occur in military/terrorist incident. Dependent on the type, strength of the actual source, degree of exposure and type of radiation different strategies may be employed to reduce damage to the body tissues. A number of pharmacological agents such as peroxisome proliferator-activated receptor (PPAR) gamma agonists, diltiazem, amifostine and palifermin as well as antioxidants and metabolic compounds have been shown to be effective in preventing and also in reducing the long-term damage of the exposure of the living cells to radiation. The major drawback of synthetic (pharmacological) compounds has been that they are highly toxic at the optimum protective dose. Studies have shown that various endogenously found compounds such as L-carnitine, and its derivative acetyl-L-carnitine, are able to protect tissues and organs against various forms of toxic insult including radiation damage. The radiation-induced chronic injury may also be counteracted by other metabolic compounds with amine groups and antioxidant properties similar to the carnitines such as cysteine, 3,3’-diindolylmethane (DIM) and N-acetylcysteine. This review discuses the radioprotective compounds as well as the potential mechanism of cellular protection against radiation by carnitines and other compounds.
All living organism from viruses, bacteria to complex plants and animals are subjected to constant background radiation from the earth itself and also from the cosmos (
The damage to living cells depends on the type of radiation (e.g. ionizing or non-ionizing), its strength and degree of exposure. The degree of exposure will depend on the time that the cell or organism is exposed; the distance from the radiation source and whether there is some shielding (lead or other radiation absorbing material) that reduces the degree and strength of exposure. Radiation is known to have powerful carcinogen inducing effects. Indeed there is a close correlation between the level of dose received and the possibility of cancer, which was shown to be dependent quite strongly to the level or dose of radiation [
The level of damage will also depend on the type of radiation. There are two types of radiation: ionizing and non- ionizing. Both types can be harmful causing DNA damage as well as tissue damage possibly due to the formation of harmful free radicals that can provoke injury or even kill living organisms.
Radiation from certain sources causes the ionization of atoms, hence, the use of the term “ionizing radiation”. Ionizing radiation is produced from nuclear reactors, nuclear armaments, nuclear power stations, nuclear medical waste, as well as from diagnostic equipment like X-rays and CT scans. Ionizing radiation is considered the most harmful. This source of radiation energy can also get deposited inside the cell, tissues or material in a fast acute manner or it may accumulate slowly over time. This accumulated radioactive energy would be released and thereby provoke damage. The radiation energy released could excite atoms, molecules, or break molecular bonds within cells and tissues, causing potential damage to the organism. The radiation dose is the measure of the energy deposited inside cells, organs, or body. To measure the energy deposited by the different types of ionizing radiation, a term called “absorbed dose” is used. This term measures the energy deposited by the radiation in one kg of substance. The SI unit of measure is J/kg, which is also called the gray (Gy). Historically a smaller unit was used, called the rad (radiation absorbed dose).
The most common diseases linked to ionizing radiation include thyroid disease, leukemia and various cancers, anemia, bone and blood disorders, endocrine disorders, reproductive abnormalities and birth defects, kidney and liver damage, and also severely compromised immune system.
Environmental Sources |
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• Background Cosmic |
• Background Terrestrial |
Man-Made Synthetic/Enriched Sources |
• For Diagnostic and Therapeutic Purposes |
• For Use in Nuclear Industry |
• For Use in Military Purposes |
• For Use in Consumer and Other Purposes |
Non-ionizing radiation is a type of electromagnetic radiation produced by electronic devices such as televisions, cell phones. The effects of this type of radiation are still under study and remain controversial.
As discussed above the biological effects are the result of the dissipation of energy into its interaction with the biological system in the form of ionization and excitation. Thus avoidance and actual physical protection (protective clothing, mask etc.) and other measures to limit exposure are of course the first line of defense against radiation-evoked injury.
However, in many circumstances it is not possible to avoid exposure such as in medical therapy or exposure to radiation accidentally. In this case the biological consequences have to be taken into account. The biological effects could be divided into 2 broad categories:
1. Somatic Effects (e.g. mutations (cancer), or burns, skin loss, cataract);
2. Genetic Effects (e.g. mutations and chromosomal damage).
Over a long term these effects increase the rate of carcinogenesis, cataract formation, cause embryo development issues as well as affect the overall life span of the organism. The type of disease outcome depends generally on the level of tissue sensitivity to radiation damage which can be summarized by the Law of Bergonie’ and Tribondeau who said that the level of differentiation of the cells, with the poorly differentiated and rapidly dividing being the most resistant to radiation and that highly differentiated and slowly dividing cells are more resistant to radiation [
Taking the above definition into account the tissues that are the most sensitive to radiation damage include the following:
1. Cells in circulation, e.g. blood cells and lymphocytes.
2. The epithelial tissues.
3. Intestinal crypt cells.
4. Cells of the reproductive system, e.g. sperm, oocyte, fetal developing cells.
5. The lens of the eye.
6. Thyroid gland.
The thyroid gland is particularly susceptible to radiation damage since it accumulates iodine and may therefore accumulate any radioactive iodine following accidental exposure, e.g. in the event of a nuclear accident. In this case potassium iodide pills can be taken to prevent the uptake of radioactive iodine. Supplementing with potassium iodine (KI) in either pill form or saturated liquid form (super saturated potassium iodide or SSKI), is the best way to quickly load iodine into the thyroid. KI can also be administered in prophylactic doses within 24 hours of exposure in case of radiation emergencies.
In the 1940’s French researchers, Latarjet and Ephrati, showed that it was actually possible to protect all the biological systems of the body, including all the various tissues and organs, not just the thyroid, from radiation- evoked damage [
Further research by various groups has shown that pretreatment with other chemical compounds such as 2- mercaptopropionylglycine (2-MPG) [
A number of pharmacological compounds have also been shown to have radioprotection properties. Thus diltiazem, acalcium antagonist with a benzothiazepine structure, was found to protect mice against a lethal (LD100) gamma radiation dose allowing a very high number of animals (up to 93%) to survive [
The major drawback of synthetic (pharmacological) compounds has been that they are highly toxic at the optimum protective dose. Therefore, it is better to use other materials, which are less toxic and offer high protection. Plants and naturally found endogenous molecules such as carnitine have been evaluated as promising sources of radioprotectors because of their low toxicity compared to synthetic thiol compounds and pharmacological agents [
Carnitine (3-hydroxy-4-N-trimethylammonium butyrate) and its acetylated derivative, acetyl-L-carnitine are com- pounds that are endogenously found in the body (
Mitochondrial metabolic defects could affect the electron transport, the tricarboxylic acid cycle, and substrate transport. However, it is the escape of oxygen free radicals (superoxide formation) as a result of a disturbed electron transfer within the respiratory chain that is thought to underlie much of the deleterious effects of mitochondrial dysfunction [
L-carnitine is found in the blood but it does not bind to plasma proteins (fraction unbound = 1) [
Thus, L-carnitine which is an endogenous mitochondriotropic substance is used in therapy to replace depleted levels, resulting in restoration of normal cellular functions and hence maintaining normal body health. Furthermore both L-carnitine and its acetylated form, acetyl-L-carnitine, demonstrate antioxidative properties, protecting cells against lipid peroxidation and membrane breakdown [
Studies in preclinical animal models showed the protective effects of the carnitines against exposure of various tissues and organs to different types of ionizing radiation (review [
The study by Dokmeci [
L-carnitine (100 mg/kg/day, i.p.) for 5 days was able to prevent radiation-induced cochlear damage after total cranial irradiation in Guinea pigs [
In a rat model of gamma irradiation a single dose to total cranium (IR) led to a significant increase in oral mucositis, MDA levels and a decrease in superoxide dismutase (SOD) and catalase (CAT) activities [
L-carnitine 100 mg/kg, i.p. pre- and post-treatment (1 day before irradiation and for 10 d after) was found to protect against the radiation-induced cataracts in lens in rats [
L-carnitine was able to prevent gamma radiation damage in active tissue with rapidly dividing cells like the seminiferous tubules [
Preclinical model of protection against ionizing radiation | ||
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Compound | Tissue/Organ Examined | Reference |
L-carnitine | Plasma, liver and erythrocytes | Dokmeci et al., 2006 [ |
Cochlear damage | Altas et al., 2006 [ | |
Oral mucositis and myelosuppression | Ucuncu et al., 2006 [ | |
Eye cataracts | Kocer et al., 2007 [ | |
Brain and retinal damages | Sezen et al., 2008 [ | |
Testis-seminiferous tubules damage | Topcu-Tarladacalisir et al., 2009 [ | |
Testicular damage | Kanter et al., 2010 [ | |
Kidney damage | Caloglu et al., 2009, Cosar et al., 2011 [ | |
Ileal mucosal injury | Caloglu et al., 2012 [ | |
Acetyl-L-carnitine | Lung and liver | Mansour, 2006 [ |
Whole body effects and mortality | Babicová et al., 2013 [ |
with relatively normal structure and resumption of complete spermatogenesis after 21 days [
Another organ that was found to be protected against radiation-induced damage was the kidney [
The administration of L-carnitine (300 mg/kg) given 30 min beforetotal abdomen irradiation was found to partially protect against acute small intestinal toxicity having effect mainly on the vascular structure [
The acetylated derivative of L-carnitine, acetyl-L-carnitine (250 mg/kg, i.p. for 5 consecutive days and 1 h after the last dose) was also found to be effective in gamma-irradiation-induced oxidative damage in liver and lung tissue after total body irradiation with a single dose [
Various other compounds with putative antioxidant and metabolic activity have also been reported to be effective in protecting against radiation-induced chronic injury [
A number of compounds from plants sources have been shown to be effective radioprotectors [
As mentioned before the mechanism underlying ionizing radiation-induced damage has a lot in common with other metabolic stress and age-related disease processes [
Thus protective strategies concentrate on compounds able to:
1) Protect against protein misfolding and enhancing DNA repair;
2) Protect against cellular and organelle damage by antioxidants;
3) Protect and enhance mitochondrial energy production.
Radiation is a phenomenon that has influenced life on earth since its evolution. Indeed nature has found various strategies to limit its damaging effects in all living organisms. The extreme form of this protective strategy is seen in certain strains of bacteria. For example in Deinococcus radiodurans and other bacteria which are ex- tremely resistant to ionizing radiation as well ultraviolet radiation [
The Deinococcus radiodurans achieves its remarkable resistance to these extreme levels of radiation by having multiple copies of its genome and by having rapid and highly efficient DNA repair mechanisms. It is the unrepaired DNA double-strand breaks (DSBs) that are thought to be the main the cause of ionizing radiation- induced cell-killing. This gives the Deinococcus radiodurans and other organisms from this genus the extraor- dinary resistance to the lethal and mutagenic effects of ionizing and u.v. radiation and to many other agents that are toxic via DNA damage. However, it has been shown that there is large variation in radiosensitivity among bacterial species which correlates not to the initial damage to the DNA but rather with the susceptibility of their proteins to radiation-induced oxidation and the actual resulting extent of protein damage [
In case of the actual protein the oxidation and/or resulting misfolding not only creates functional issues, for example if it is an enzyme or transporter protein it will not be able to carry out its function, but may transform certain proteins into more toxic forms [
Many studies have shown that both L-carnitine and acetyl-L-carnitine are able to reduce the damage to the lipids due to peroxidation and thereby reduce the radiation-evoked MDA generation. They also increase the levels of the intracellular antioxidant enzymes, SOD and glutathione and catalase. Both compounds have been reported to possess antioxidant properties but in particular they reduce the generation and the release of the extremely toxic free radicals from the mitochondria that is increased when the respiratory chain in the mitochondria and the mi- tochondrial membranes are compromised [
Most of the cellular energy in eukaryotic cells comes from the generation of high energy phosphate bonds in the form of adenosine triphosphate (ATP) and the most amount of cellular ATP is generated within the mitochondria. The net amount of energy equivalents to be obtained from a molecule of glucose is about 30 ATP whereas the beta oxidation of a fatty acid like palmitate produces 106 ATP. For beta oxidation of the fatty acids the molecule of fatty acid has to first be transported across the inner mitochondrial membrane and this can only occur in the presence of L-carnitine which actually binds to the fatty acids thereby permitting its movement into the mitochondria. Thus, although L-carnitine is a relatively simple molecule, it can greatly influence cellular energy production by facilitating beta-oxidation [
In recent years studies have shown that the cellular damage induced by radiation can be reduced by using particular compounds. Strategies are being developed to protect tissues and organisms not only from accidental radiation exposure such as in possible war or terrorist attack but also from pathological changes induced in normal tissues following radiotherapy for cancer [
Another common side effect of radiation exposure and especially in cancer therapy is fatigue [
Strategies exist for counteracting the damaging effects to either accidental or therapeutic exposure to radiation. These include the administration of protective compounds such as L-carnitine and acetyl-L-carnitine as well as other compounds. The replenishing the carnitine pool by systemic administration of L-carnitine has been found to be beneficial in reducing the side effects of radio chemotherapy [
We are grateful to Mrs. Antoinette Celli for her help with the grammatical revision of the manuscript.