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"Radiosensitisers and Radioprotectors"

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Effective dose(experimental): Optimum dose of for protection is 20mg/kg i.p. in mice(it is far below its toxic dose)[1], [2], [3].
MPG 250 mg intravenously has been successfully given to cervical cancer patients[3].
It is mentioned in an article that MPG can be given to man with a dose comparable both to mice and man[3]
Mode of administration: Intraperitoneal[3].
Oral administration[4]is effective in humans[1].
Intravenous administration [5];however Tiopronin serious adverse reactions are more common in intravenous administration, the injection can cause parotid gland swelling, even anaphylactic shock[6].
Intragastric and intraperitoneal modes also offered radioprotection and radiomitigation[7].
Time of administration: Effective when applied both before and 1-5 hrs after irradiation(animal data)[8]
In majority of experiments it is found to be administered before irradiation[49],[50],[51]; however in an clinical evaluation with cervical patients ,significant radioprotection is obtained when MPG is given 15-20 minutes after irradiation[3]
Side Effects: Frequent:
Pain, swelling, tenderness of skin, rash, hives, itching, oral ulcers.
Occasional :
GI upset, taste or smell impairment, bloody or cloudy urine, chills, difficulty in breathing, high blood pressure, hoarseness, joint pain, swelling of feet or lower legs, tenderness of glands.
Rare :
Chest pain; cough; difficulty in chewing, talking, swallowing; double vision; a general feeling of discomfort; illness; weakness; muscle weakness; spitting up blood; swelling of lymph glands[4].
Combinatorial action with other drugs/therapies: Tiopronin is shown to increase the sensitivity of multiple drug resistant human cancer cells lines to certain chemotherapeutic drugs like etoposide, adriamycin[9], [10].
It antagonizes the mitogenic effect of Prolactin on the MCF-7 human breast cancer cell line, at non-toxic concentrations [11].
Pretreatment with either MPG or WR-77913 individually, or in combination could prevent the depletion in liver GSH levels and induction of lipid peroxidation after cyclophosphamide chemotherapy [12]; however in human lymphocytes and in polychromic erythrocytes of mice, it did not offer protection against damage caused by bleomycin and cyclphosphamide [13].
Ascorbic acid and MPG when given together, appearance Ehrlich-Heinz bodies in human venous red cells following in vitro intoxication was retarded [14].
In a study involving 110 patients, the combined application of Yinqin Ginggan Decoction (YQD) with tiopronin achieved good effect in the treatment of Alcohol Liver Disease (ALD) [15].
Studies in animals-
Combination of WR-2721 and 2-mercaptopropionylglycine is seen to be superior to the single-drug treatments in reducing GI injury and increasing survival [2]. This combination was also helpful in mitigating WR-2721 toxicity on mouse bone marrow chromosomes [16], [17]. Combination of these two at different doses as well as at different time of administration influences the overall effect [18]. Administration of 2-MPG after WR-2721 resulted in elevated levels of blood GSH for longer duration in normal and irradiated animals[17].
2-MPG exerts its hepatoprotective activity against isoniazid[19] and Adriamycin[20]induced hepatotoxicity and cardiotoxicity in rats by inhibiting the oxidative toxicity of drug and in Hela and RL♂1 tumor-bearing mice, nullifies the free radicals generated by antitumor drugs - Neocarzinostatin and SMANCS [21].
Cysteamine and MPG in combination is shown to be effective in reducing radiation(lower doses) induced prenatal mortality(decreased percentage of dead and resorbed embryos in mice[22].
Tiopronin alone in Wistar rats [23] as well as its combination with alpha tocopherol in albino gunia pigs showed to slow down the progression of cisplatin induced cochlear damage [24]. In rats, protective effects of tiopronin on cisplatin-induced nephotoxicity is also observed in vitro and in vivo with no reduction in antitumor activity of cisplatin[25], [26].
Complexing of Zn (II) with 2-MPG significantly enhanced its radioprotective activity in mice [27]. MPG with low dose radiation showed apparent radiosensitization of enzyme catalase owing to circumstantial interaction of MPG with Fe++/Fe+++ [28].
In mice MPG treatment in combination with suboptimal doses of AET did not recover leucocytopenia due to whole body gamma irradiation (760R and 1060R) [29] as well as survival of mice also couldn’t be achieved [30] ; in contrast, combined administration of MPG and aminothiols(AET, MEA, cysteine) before irradiation resulted in a synergistic radioprotective effect [8],[31] but when AET was given before irradiation and MPG after, no increase in effectiveness was found[31]; In investigators’ opinion, the contrast in results may be attributed to differences in dose rate, direction of irradiation, strain of animals and some environmental conditions[30].
HT (hydroxytryptophan) + MPG treatments though have failed to prevent the initial 59Fe uptake depression induced by the irradiation, have helped a speedy recovery in the iron uptake[32], the combination offered protection against whole body irradiation(against 10.5Gy but not against 12.5 Gy)[33].
An increase in radioprotection with increasing concentrations of MPG in the presence of EDTA at 266.4 Gy was observed[34].
Gold nanoparticles protected with Tiopronin and functionalized with Tat peptides is shown to be used to target nucleus [35]. Assembly of gold nanoparticles and tiopronin is shown to have cytotoxic effect on cancer cell lines[36].
Protection to mice bone marrow stem cells has been noted after whole body gamma ray exposure by prior treatment with combination of hydroxytryptophan (HT) and B-mercaptopropionylglycine (MPG) as studied by spleen colony forming method[37].
The preventive and therapeutic effects of (±)-tiopronin and (-)-tiopronin on leucopenia induced by cyclophosphamide were found[38].
Tiopronin combined with Vitamin E is found be clinically efficient for the treatment of alcoholic fatty liver disease[39].
MPG could reduce the leucopenia induced by some therapeutic agent like Mitomycin C, Prednisolone, Azathioprine[40].
Protected against genotoxicity induced by Potassium dichromate in mice[41]and also by benzo(a)pyrene in vitro and in vivo[42].
Contraindications: Drastic dietary changes, especially in sodium, should be avoided in cystinuria patients [43]. Fluid intake should be increased to maintain urine pH at a normal range of 6.5-7[4].
Caution is warranted with a history of penicillamine exposure; serious adverse reactions are more likely to occur[44], [4].
It is also contradicted in patients with history of agranulocytosis, aplastic anemia, or thrombocytopenia and hypersensitivity to tiopronin or its components[4].
An acute anti-hypertensive effect of anti-oxidant agent-thiopronine in hypertensive subjects and in both hypertensive and non-hypertensive diabetic patients is reported[45].
In one study, it appeared to be safe to administer tiopronin in patients with slight to moderate renal impairment [46].
A study indicated that Patients treated with tiopronin should be monitored for proteinuria[47]and also for the development of lipid abnormalities[48].
1. Nagata H, Chapter 3:Protection against radiation-induced damage - experimental radioprotection; In: Modification of Radiosensitivity in Cancer Treatment, edited by Tsutomu Sugahara, Academic Press, Japan, 1984, page 39.
2. Prasanna PG, Uma Devi P, Modification of WR-2721 radiation protection from gastrointestinal injury and death in mice by 2-mercaptopropionylglycine, Radiat Res. 1993;133(1):111-5.
3. Sugahara T, Horikawa M, Hikita M, Nagata H, Studies on a sulfhydryl radioprotector of low toxicity, Experientia Suppl. 1977;27:53-61.
4. Tiopronin, Individual drug monographs, 2014 by Mosby, Inc., an imprint of Elsevier Inc.
5. Carlsson SM, Denneberg T, Emanuelsson BM, Kågedal B, Lindgren S, Pharmacokinetics of intravenous 2-mercaptopropionylglycine in man, Eur J Clin Pharmacol. 1990; 38(5):499-503.
6. Li Xiaodong, Lu Xi Ming, Lu Wenjuan, Applicant- Pharmaceutical Co., Ltd., Suzhou two leaves, Tiopronin enteric capsule prescription and preparation process thereof, 2012, publication number CN 102552207 A, Google patent.
7. Xia Wei,Sun Wen-xin,Zhang Chang-zheng et al., Preventive and Therapeutic Effect of Tiopronin on Leukopenia Induced by Radiotherapy in Mice, Henan Journal Of Oncology, 2000-04.
8. Sántha A., Mándi E., Benkó G. and Bodó S. Z. Proceedings: The radioprotective effect of alpha-mercaptopropionylglycine and its combinations on animals, Br J Cancer. 1975 December; 32(6): 768.
9. Goldsborough AS, Handley MD, Dulcey AE, Pluchino KM, Kannan P, Brimacombe KR, Hall MD, Griffiths G, Gottesman MM., Collateral sensitivity of multidrug-resistant cells to the orphan drug tiopronin, J Med Chem. 2011;54(14):4987-97.
10. Authenticated US Government Information, Federal Register/Vol. 76, No. 54/Monday, March 21, 2011/Notices, page 15327.
11 Malamas FM, Thomas CG, Stefos T, Evangelou A., Effects of sulfhydryl compounds on cancer cell lines: I: N-(2-Mercaptopropionyl)-glycine exerts antiproliferating effects and antagonizes the stimulating effect of prolactin on MCF-7 human breast cancer cells, In Vivo. 2007; 21(2):329-32.
12. Bhanumathi P, Devi PU., Modulation of glutathione depletion and lipid peroxidation by WR-77913 an 2-mercaptopropionylglycine in cyclophosphamide chemotherapy, Indian J Exp Biol. 1994;32(8):562-4.
13. Formigli LM, Ferrari I, Grisolia CK, Evaluation of genotoxic and cytotoxic potential of thiola (N-2-mercaptopropionylglycine), a medicine used in the treatment of humans contaminated with mercury, Environ Mol Mutagen. 2002; 39(1):18-21.
14. Germanò D, Abbate C, Granata A, Erythrocyte protective synergism of ascorbic acid and alphamercaptopropionylglycine, Minerva Med. 1979;70(38):2615-9.
15. Zhang Ya-xi1,Yang Chun-hua2,Zhou Li1,Fu Jing-xia, Clinical study on Yinqin Qinggan decoction combined with tiopronin in treating alcoholic liver disease, Chinese Journal of Integrated Traditional and Western Medicine on Digestion, 2010-06.
16. Thomas B, Devi PU, Chromosome protection by WR-2721 and MPG-single and combination treatments, Strahlenther Onkol. 1987; 163(12):807-10.
17. 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.
18. Bisht KS, Uma Devi P, Jagetia GC, Kamath G., Drug combination against single drug treatment in radiation protection of the bone marrow CFU, Strahlenther Onkol. 1990;166(8):545-8.
19. 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.
20. El-Missiry MA, Othman AI, Amer MA, Abdel-Aziz MA, Attenuation of the Acute Adriamycin-induced Cardiac and Hepatic Oxidative Toxicity by N-(2-Mercaptopropionyl) Glycine in Rats, Free Radic Res. 2001;35(5):575-81.
http://dx.doi.org/ 10.1080/10715760100301581
21. Oda T, Yamamoto H, Miki T, Maeda H., Differential neutralizing effect of tiopronin on the toxicity of neocarzinostatin and SMANCS: a new rescue cancer chemotherapy, Jpn J Cancer Res. 1989;80(4):394-9.
22. 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.
23. Fetoni AR, Quaranta N, Marchese R, Cadoni G, Paludetti G, Sergi B, The protective role of tiopronin in cisplatin ototoxicity in Wistar rats, Int J Audiol. 2004; 43(8):465-70.
24. Fetoni AR, Sergi B, Ferraresi A, Paludetti G, Troiani D, Protective effects of alpha-tocopherol and tiopronin against cisplatin-induced ototoxicity, Acta Otolaryngol. 2004; 124(4):421-6.
25. Zhang JG, Lindup WE, Tiopronin protects against the nephrotoxicity of cisplatin in rat renal cortical slices in vitro, Toxicol Appl Pharmacol. 1996; 141(2):425-33.
26. Zhang JG, Viale M, Esposito M, Lindup WE., Tiopronin protects against the nephrotoxicity of cisplatin in the rat, Hum Exp Toxicol. 1999; 18(12):713-7.
27. Zhou X., Phadtare S., Agrawal K.C., Kishore V., Synthesis and radioprotective effect of Zinc(II) complexes with cyteamine, cysteine and mercaptopropionylglycine, Pharm. Pharmacol. Commun 2000; 6,299-302.
28. Wary KK and Sharan RN, Effect of the radioprotector 2-mercaptopropionyl glycine (MPG) on the radiation inactivation of catalase in vitro, J. Radiat. Res. 1988, 29, 104-109.
29. Ghose A, Pant RD, Effect of 2-mercaptopropionylglycine and 2-aminoethyl isothiuronium bromide hydrobromide on leucocytes in peripheral blood after gamma ray exposure in mice, J Radiat Res. 1981;22(4):381-6.
30. Ghose A and Srinivasan MN, Ineffectiveness of 2-Mercaptopropionylglycine in increasing survival of mice after gamma irradiation either alone or in combination with 2-Aminoethyl isothiuronium bromide hydrobromide, J. Radiat. Res. 1980, 21, 197-203.
31. Giamberrasi l, Jacobs A, Radioprotectants ; In Military Radiobiology edited by James Conklin and Richard Walker, 1987, Academic Press, Florida, Page 292.
32. Ghose A, Basu SK, Ganguly SK, Bhatnagar A, Mathur M., Role of some radioprotectors on 59Fe uptake in bone marrow after whole-body gamma irradiation to mice, Strahlentherapie. 1983; 159(12):772-4.
33. Ghose A, Ganguly SK, Kaur J, Protection with combinations of hydroxytryptophan and some thiol compounds against whole-body gamma irradiation, Int J Radiat Biol Relat Stud Phys Chem Med. 1983;44(2):175-81.
34. Ayene SI, Srivastava PN., Radioprotective effect of 2-mercaptopropionylglycine on radiation induced microsomal lipid peroxidation, Int J Radiat Biol Relat Stud Phys Chem Med. 1985; 48(2):197-205.
35. De la Fuente JM, Berry CC, Tat peptide as an efficient molecule to translocate gold nanoparticles into the cell nucleus, Bioconjug Chem. 2005,16(5):1176-80.
36. Cui L, Zahedi P, Saraceno J, Bristow R, Jaffray D, Allen C, Neoplastic cell response to tiopronin-coated gold nanoparticles, Nanomedicine. 2013, 9(2):264-73.
37. Dey J, Dey TB, Ganguly SK, Nagpal KK, Ghose A, Chemical radioprotection to bone marrow stem cells after whole body gamma irradiation to mice, Strahlenther Onkol. 1988; 164(11):681-3.
38. Xie Pei,Yan Tian-hua,Wang Qiu-juan,Guo Qing-long, Effects of tiopronin on leukopenia induced by radiation and cyclophosphamide in mice, Chinese Journal of Biochemical Pharmaceutics, 2010-03.
39. Zhan Guo-qing,LI Sheng-jun,Zhou Hong et al., A clinical observation on the efficacy of tiopionin combined with Vitamin E for alcoholic fatty liver disease, Chinese Journal of Clinical Hepatology, 2008-06.
40. Mori H, Nagai H, Koda A, Effect of alpha-mercaptopropionylglycine (alpha-MPG) and sodium dipropylacetate (DPA) on antibody formation (II). Immunosuppression induced by carcinostatic agents and glucocorticoid (author's transl), Nihon Yakurigaku Zasshi. 1978; 74(6):653-61.
41. Fahmy MA, Shoman HM, Hassan EE, The protective role of thiola and soybean seeds against the genotoxicity induced by potassium dichromate in mice, Mutat Res. 2002;517(1-2):1-12.
42. Galdean D, Petrasincu D, Alangiu P, Ibric S, Voiculetz N, The protective effect of Thiola against the genotoxic action of benzo(a)pyrene, Experientia. 1986; 42(5):572-4.
43. Lindell A, Denneberg T, Edholm E, Jeppsson JO, The effect of sodium intake on cystinuria with and without tiopronin treatment, Nephron. 1995; 71(4):407-15.
44. Matsukawa Y, Saito N, Nishinarita S, Horie T, Ryu J, Therapeutic effect of tiopronin following D-penicillamine toxicity in a patient with rheumatoid arthritis, Clin Rheumatol. 1998; 17(1):73-4.
http://dx.doi.org/ 10.1007/BF01450965
45. Ceriello A, Giugliano D, Quatraro A, Lefebvre PJ, Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects, Clin Sci (Lond). 1991; 81(6):739-42.
46. Carlsson MS, Denneberg T, Emanuelsson Britt-Marie, Kågedal B, Lindgren S , Pharmacokinetics of 2-mercaptopropionylglycine (Tiopronin) in patients with impaired renal function, Drug Investigation 1994;7(2): 101-112.
47. Alvarez NR, Vidau AP, Rodríguez SC, Herrera PJ, Suarez HM, Nephrotic syndrome and anasarca status, secondary to treatment with tiopronin in a case of cystinuria, Arch Esp Urol. 2001;54(5):438-40.
48. Siskind MS, Popovtzer MM, Hyperlipidemia associated with alpha-mercaptopropionylglycine therapy for cystinuria, Am J Kidney Dis. 1992;19(2):179-80.
49. Uma Devi P et al, Radioprotective effect of 2-mercaptopropionylglycine on the intestinal crypt of Swiss albino mice after cobalt-60 irradiation. Radiat Res. 1979 Oct;80(1):214-20.
50. Saini MR et al, Radiation protection of mouse liver by 2-mercaptopropionylglycine. J Radiat Res. 1977 Aug;18(3):206-10.
51. Uma Devi P, Surana M, Chemical modification of adrenal response to external whole body irradiation in mice. Acta Radiol Oncol. 1985 Sep-Oct;24(5):427-31.