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"Radiosensitisers and Radioprotectors"

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Drug Action: It significantly protects leukocytes against radiation-induced damage in man[1]
Molecular Targets: Lipids
MPG protects lipid from peroxidation[2] and also unsaturated fatty acids of membrane[3], lipid bilayer of liposomes, microsomes[4] ; however a study showed that 2-MPG stimulated NADPH-dependent lipid peroxidation by rat liver microsomes[5]. MPG at relatively low and non-toxic concentrations can inhibit the oxidation of lipids associated with ischemia/reperfusion injury of the lung [6].
Nucleic Acids
MPG protects DNA strands [7],[8],[9]chromosomal injury[10].Radiation induced(39 Gy and 91 Gy) single-strand breaks were reduced by MPG (10mM, 20mM)in presence of oxygen; but the reduction is found to be smaller under oxic conditions[11]; however it is not supported by another study where 0.02mM MPG did not offer significant radioprotection for radiation induced (500 R) DNA single-strand breaks[12]. It provides consistent radioprotection against chromosome aberrations in peripheral lymphocytes in man[1].
In vitro experiments showed that MPG markedly reduced the mRNA expression and release of TNF-alpha and IL-6 in peritoneal macrophages isolated from normal rats and also in those subjected to hypoxia and reoxygenation[19].
It declines levels of expression of the c-myc and c-fos[13] as well as as c-jun and ca-Ha-ras mRNA genes[20] proto-oncogenes in partially hepatectomized rat livers.
It brings about the reduction in the level of iNOS mRNA[14].
MPG is hypothesized to interact with and disturb the structure of kinases involved in signal transduction leading to reduction in expression of proto-oncogenes in partially hepatectomized rat livers [13]. It is also found to inhibit hepatic CYP2E1[9]. MPG reduced the level of TNF protein [14], iNOS protein [15] and SOD activity in Jurkat cells and in cell-free extracts [16]. MPG suppressed the expression of cellular marker proteins for oxidative stress and inflammatory mediator MCP-1[17]. It protects stratum corneum from UV-irradaition[18]. MPG at relatively low and non-toxic concentrations can inhibit the oxidation of tissue sulfhydryls, soluble protein[6].
Mechanism: A study has shown that the protective action of MPG may not be at the level of primary cell death but at the later stage of recovery leading to an early resumption of mitosis and an accelerated regeneration[21],[22],[7], also shown to protect stem cells and thereby accelerating the recovery[23]; in contrast, a study on lymphocyte concluded the MPG protected cells from direct killing , thus reducing the initial depletion and it also protects chromosome by restitution[24].
Metabolic inhibition is suggested as possible mechanism of action of a drug[25],[26]. It is potent free radical inhibitor[27] and scavenger[6] and also hydrogen peroxide scavenger[28], in vitro superoxide (O2-) scavenger[29], [30] and not in vivo (O2-) scavenger[28], Peroxynitrite and hydroxyl(OH-) radical scavenger[31]; however it is unable to interfere with the oxidants produced by myoglobin-H2O2 system[32]. Thiopronin may reduce the production of free radicals via inhibition of hepatic CYP2E1 and increase the removal of free radicals directly [9]or through the induction of cytosolic GSTs[33].
It is powerful super oxide synthesis inhibitor[34]-
2-MPG prevents the abnormal production of xanthine oxidase[35], which acts a source of superoxide [36], hydrogen peroxide and ultimately generates reactive oxygen species[37].
The primary effect of N-(2-mercaptopropionyl)glycine is to capture G(.+) centers, that is, guanine radical cations and thus it can either prevent or repair radiation damage to DNA [38].
It affects cell proliferation by modulating(declining) the expression of the proto-oncogenes like c-myc and c-fos [13] as well as c-jun and ca-Ha-ras mRNA genes[20] in partially hepatectomized rat livers may be by disturbing the secondary structure of kinases involved in signal transduction and thus disturb the whole series of events leading to activation of protooncogene expression or may be increasing the level of some destabilizing factor and the proteins of anti-oncogenes[13], [20].
High redox potential of MPG may result in a long-lasting release of sulphydryl compunds from proteins, which would lead to increase the concentration of natural radioprotective substances in the cell and ultimately to increased radioresistance[7].
2-MPG alone or in combination was also found to be maintaining the blood glutathione levels which act as endogenuous radioprotector i.e. it is possible that MPG delays the metabolism of GSH[39]. This replenishment of GSH is also found to lessen the lipid peroxidation[40]. Macromolecular free radical like lipid radical (L.) formed in a cellular target either by direct or indirect action, is restored or repaired by labile hydrogen atom, transferred from the SH groups of MPG ® L.+ RSH =LH +RS. .Thus, unsaturated fatty acid (LH) is repaired. This process arises because the SH bond energy in thiols is only 382 ± 6 KG mol, while the CH bond energy is somewhat higher. Thiyl radical (RS.) is considered to be unreactive and disappear mainly via diffusion controlled recombination to disulphide ® RS. + RS. = RSSR. This mechanism of radiation protection stops the propagation of free radical formation from unsaturated fatty acid and protects the membranes and organelles from destruction [3]. Presence of 2-MPG decreased formation of MDA and lipid hydroperoxides. This action of the drug is thought to be due to conversion of hydroperoxy to hydroxyl fatty acids within lipid bilayer, as well as the scavenging action on initiating free radicals[4].
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2. Ayene SI, Kale RK, Srivastava PN, Radioprotective effect of 2 mercaptopropionyl glycine on radiation induced lipid peroxidation and enzyme release in erythrocytes, Int. J. Radiat. Biol. 1988; 53(4): 629-639.
3. Sharma P. and Saini MR, Modification of Radiation Induced Prenatal Mortality by Cysteamine, MPG and their Combination in Swiss Albino Mice, Ind. J. Nuc. Med. 2003;18(1 & 2): 12-18.
4. Garner A, Jamal Z, Slater TF, Effects of 2-mercaptopropionyl glycine on radiation-induced lipid peroxidation in liposomes and in rat liver microsomal suspensions, Int J Radiat Biol Relat Stud Phys Chem Med. 1986;50(2):323-35.
5. Harata J, Nagata M, Ishiguro I, Ohta Y, Effect of 2-mercaptopropionylglycine on lipid peroxidation and drug oxidation in rat liver microsomes, Biochem Int. 1984;8(1):49-59.
6. Ayene IS, al-Mehdi AB, Fisher AB., Inhibition of lung tissue oxidation during ischemia/reperfusion by 2mercaptopropionylglycine, Arch Biochem Biophys. 1993; 303(2):307-12.
7. Devi PU, Saini MR, Saharan BR and Bhartiya HC, Radioprotective Effect of 2-Mercaptopropionyl glycine on the Intestinal Crypt of Swiss Albino Mice after Cobalt-60 irradiation, Radiation Research 1979,80, 214-220.
8. Geist JR, Shupe RE, Kafrawy AH, Evaluation of chemical protection against radiogenic osteodentin synthesis. J Oral Pathol 1988; 17: 26-29.
9. Yue J, Dong G, He C, Chen J, Liu Y, Peng R, Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats, Toxicology. 2009;264(3):185-91.
10. Gupta R. and Devi UP, Protection against radiation induced chromosome injury by sulfhydryl compounds, Acta Radiol Oncol., 1985; 24(5):419-25.
11. Modig HG, Edgren M, Révész L, Effect of radioprotective aminothiols on the induction and repair of single-strand breaks in the DNA of irradiated mammalian cells, Acta Radiol Ther Phys Biol. 1977;16(3):245-56.
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18. van den Broeke LT, Beyersbergen van Henegouwen GM, UV-radiation protecting efficacy of thiols, studied with UVA-induced binding of 8-MOP and CPZ to rat epidermal biomacromolecules in vivo, Int J Radiat Biol. 1993;63(4):493-500.
19. Tamion F, Richard V, Bonmarchand G, Leroy J, Hiron M, Daveau M, Thuillez C, Lebreton JP, Reduced synthesis of inflammatory cytokines by a free radical scavenger after hemorrhagic shock in rats, Crit Care Med. 2000;28(7):2522-7.
20. Sharma D, Radhika S., Muralidhar K., Dixit A, 2-Mercaptopropionylglycine modulates the expression of c-jun and c-Ha-ras in regenerating rat liver, Cancer Letters 1995;93: 201-205.
21. Devi PU and Saini MR, Protection of Mouse Thymus against Cobalt-60 Radiation by 2-Mercaptopropionylglycine (MPG), J. Radiat. Res. 1977, 18, 211-224.
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23. Saini MR, Devi PU., Radiation protection of pronormoblasts and normoblasts by 2 mercaptopropionylglycine (MPG), Experientia. 1980; 36(4):448-9.
24. Saini MR, Devi PU, Yadav SS, Radiation protection of bone marrow lymphocytes by 2-mercaptopropionylglycine (MPG), Experientia. 1978 Dec 15; 34(12):1627-8.
25. Devi PU, Jagetia GC, Effect of 2-mercaptopropionylglycine (MPG) on thyroid function in sub-lethally irradiated mice, Experientia. 1981; 37(3):312-3.
26. Kumar A, Devi PU, Chemoprotection of ovarian follicles of mice against gamma irradiation by MPG (2-mercaptopropionylglycine), J Radiat Res. 1982; 23(3):306-12.
27. Rommain M, Delecoeuillerie G, Paul JL, Raichvarg D, Inhibitory action of tiopronin on free radicals, Rev Rhum Mal Osteoartic. 1989; 56(5 Pt 2):34-7.
28. Horwitz LD, Fennessey PV, Shikes RH, Kong Y., Marked reduction in myocardial infarct size due to prolonged infusion of an antioxidant during reperfusion, Circulation. 1994; 89(4):1792-801.
29. Mitsos SE, Fantone JC, Gallagher KP, Walden KM, Simpson PJ, Abrams GD, Schork MA, Lucchesi BR., Canine myocardial reperfusion injury: protection by a free radical scavenger, N-2-mercaptopropionyl glycine, J Cardiovasc Phramacol, 1986;8(5):978-88.
30. Westlin W, Mullane K, Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals?, Circulation. 1988; 77(6 Pt 2):130-9.
31. Saini-Chohan HK, Dhalla NS., Attenuation of ischemia-reperfusion-induced alterations in intracellular Ca2+ in cardiomyocytes from hearts treated with N-acetylcysteine and N-mercaptopropionylglycine., Can J Physiol Pharmacol. 2009; 87(12):1110-9.
http://dx.doi.org/ 10.1139/Y09-103
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33. Konstantinova MM, Revez L, Comparative study of the radioprotective activity and mechanism of action of 2-mercaptopropionylglycine and beta-mercaptoethylamine, Radiobiologiia. 1977; 17(6):839-43.
34. Atmaca Gulizar, Antioxidant effects of Sulfur-Containing amino acids, Yonsei Medical Journal 2004; 45(5): 776-788.
35. Abdo EE, Machado MC, Coelho AM, Sampietre SN, Leite KR, Molan NA, Pinotti HW, Antioxidative effect of N2-mercaptopropionylglycine (N2 MPG) in experimental acute pancreatitis, Rev Hosp Clin Fac Med Sao Paulo. 1998; 53(4):169-73.
36. McCord JM, Oxygen-derived free radicals in postischemic tissue injury, N Engl J Med. 1985; 312(3):159-63.
37. Lacy F, Gough DA, Schmid-Schönbein GW, Role of xanthine oxidase in hydrogen peroxide production, Free Radic Biol Med. 1998;25(6):720-7.
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39. Devi PU and Prasanna PG, Radioprotective effect of combinations of WR-2721 and Mercaptopropionylglycine on mouse bone marrow chromosomes, Radiat. Res. 1990;124, 165-170.
40. Tripathi Y, Hegde BM, Rai YS, Raghuveer CV, Effect of N-2-mercaptopropionylglycine in limiting myocardial reperfusion injury following 90 minutes of ischemia in dogs, Indian J Physiol Pharmacol. 2000;44(3):290-6.