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2-mercaptopropionylglycine

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General Features                  Clinical Study                  Chemical Intervention                 Pharmacological Aspects                 
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TOXICITY

Toxicity values: LD50 mouse iv= 2100mg/kg[1].
LD50 mouse ip = 3020mg/kg[2].
Adverse reactions: thiopronine produced a significant hypotensive effect at a dose of 12 mmol[3].
Abnormalities developed like proteinuria[4], hyperlipidemia usually subsided after withdrawal of drug[5], [6], [7], also the side effects observed with MPG disappear when treatment is withdrawn [8], [9]which suggest that the effects are dose-related and accumulation of the drug in blood might be the reason[10].
A condition called Pemphigus foliaceus occurred in a cystinuria patient treated with MPG[4].
In mice, it is observed that at higher dose levels such as 100, 200,500mg/kg, 2-MPG can damage liver tissue irreversibly[11].
It is reported to induce chronic intrahepatic cholestasis[12].
Rheumatoid arthritis patients treated with tiopronin showed nephritis and dermatitis due to tiopronin[13].
A strong association between B35-Cw4 class I antigens and toxicity due to tiopronin has been disclosed by imunogenetic typing [13], [14].
Two patients developed thrombocytopenia while on tioprini[15].
2-Mercaptopropionylglycine (2-MPG) has been shown to transform normal red blood cells (RBCs) into paroxysmal nocturnal haemoglobinuria (PNH)-like RBCs in vitro, depending on the concentration, pH and time of incubation [16].
Pathological conditions observed in mouse liver during 1-14 days after injecting higher dose levels (100, 200 and 500 mg/kg body-weight) of MPG are Cytoplasmic degranulation and vacuolation, nuclear changes like pyknosis, shrinkage, necrosis, crenation and mild lymphocytic infiltration, hyperaemia, hypertypic nuclei. The damages are reversible after administration of drug upto 200mg/kg body-weight for 14 days interval studied; but after the administration of 500 mg /kg body-weight of MPG the damages are irreversible as studied upto 14 days[11].
At a high dose, thiola showed a cytotoxic effect, significantly decreasing the relative proportion of polychromatic erythrocytes of mice [17].
Long term (for 30 and 60 days) treatment of male rats with 20mg/kg/day thiola adversely affected the reproductive system [18].
Long-term tolerability study of 2-MPG (Acadione) 1gm/day on Rheumatoid Arthritis patients also revealed adverse conditions which led to discontinuation of treatment [19].
In study of long-term(average 6.3 years) treatment of cystinuria patients with 2-MPG(500 to 2500mg per day), occurrence of irreversible glomerular lesions is observed[20].
A report on development of tiopronin-induced lichenoid eruptions after 2-years of treatment with tiopronin in a woman suffering from liver cirrhosis [7].
It has been shown to have acantholytic potential [21].
Induction of severe polymyositis due to tiopronin is reported in a rheumatoid arthritis patient [22].
Tiopronin can induce Myasthenia gravis [23].
In an in vitro study, MPG induced an increasing degradation of DNA in unirradiated cells with increasing concentration and incubation time[24].
Another in vitro study revealed the inhibition of 3H-thymidine incorporation in unstimulated as well as Phytohemagglutinin (PHA) stimulated lymphocytes with increasing concentrations of alpha-mercaptopropionyl-glycine while low concentration of the drug enhanced spontaneous lymphocyte blastigenesis [25].
Mutagenicity or Carcinogenicity Data: Tiopronin has been proved to be free of mutagenic activity [26]. Thiola did not increase the frequency of chromosomal aberration in human lymphocytes[17] Suggested to have anti-carcinogenic effect against certain carcinogens [27].
Fertility: Long-term treatment of this drug to normal adult rat brought about significant decline in circulating levels of testosterone and an increase in testicular cholesterol content indicating probable inhibition of androgen synthesis. The data revealed the loss of sperm motility, reduction in fertilizability and survival of spermatozoa in cauda epididymidis[18] and also histoarchitecture of reproductive organs, level of testosterone, sperm morphology of rats after long term administration (for 30 and 60 days) of 20 mg/kg body weight/day Thiola[28].
Pregnancy: It is unknown whether tiopronin crosses the placenta[29].
Pregnancy Risk Category: C [29].
Breast Feeding: It is unknown whether tiopronin is distributed in breast milk[29].
Orally administrated 2-mercaptopropionyl-glycine was found to be suppressing Puerperal lactation and plasma prolactin levels in women in puerperium [30].
REFERENCES
1. Nagata H, Sugahara T, Tanaka T, Radiation protection by 2-mercaptopropionylglycine in mice, J Radiat. Res, 1972;13,163-166.
http://dx.doi.org/10.1269/jrr.13.163
2. 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.
http://dx.doi.org/10.1038/bjc.1975.347
3. 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.
http://www.ncbi.nlm.nih.gov/pubmed/1662579
4. Lucky PA, Skovby F, Thier SO, Pemphigus foliaceus and proteinuria induced by alphamercaptopropionylglycine, J Am Acad Dermatol. 1983; 8(5):667-72.
http://www.ncbi.nlm.nih.gov/pubmed/6863624
5. 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.
http://www.ncbi.nlm.nih.gov/pubmed/11494716
6. Siskind MS, Popovtzer MM, Hyperlipidemia associated with alpha-mercaptopropionylglycine therapy for cystinuria, Am J Kidney Dis. 1992;19(2):179-80.
http://www.ncbi.nlm.nih.gov/pubmed/1739102
7. Kurumaji Y, Miyazaki K, Tiopronin-induced lichenoid eruption in a patient with liver disease and positive patch test reaction to drugs with sulfhydryl group, J Dermatol. 1990; 17(3):176-81.
http://www.ncbi.nlm.nih.gov/pubmed/2141340
8. Ambanelli U, Manganelli P, Ferraccioli GF, Clinical efficacy and adverse effects of tiopronin in rheumatoid arthritis. Report of a follow-up in 50 patients, Z Rheumatol. 1982; 41(5):235-9.
http://www.ncbi.nlm.nih.gov/pubmed/7158085
9. Ichikawa H, Imaizumi K, Tazawa Y, Obara Y, Ishikawa Y, Tobari I, Tanabe Y, Effect of tiopronin on senile cataracts. A double-blind clinical study, Ophthalmologica. 1980; 180(5):293-8.
http://dx.doi.org/10.1159/000308990
10. Penugonda S, Wu W, Mare S, Ercal N., Liquid chromatography analysis of N-(2-mercaptopropionyl)-glycine in biological samples by ThioGloTM3 derivatization, J Chromatogr B Analyt Technol Biomed Life Sci. 2004;807(2):251-6.
http://dx.doi.org/10.1016/j.jchromb.2004.04.019
11. Saharan BR, Singh RP, Verma A., Toxicity of 2-mercaptopropionylglycine (MPG) on mouse liver, J Radiat Res. 1977; 18(4):302-7.
http://dx.doi.org/10.1269/jrr.18.302
12. Hewitt, Toxicology of the Liver, Second Edition edited by Gabriel L Plaa, WR Hewitt, page 12-13.
http://books.google.co.in/books?isbn=1439810443
13. Ferraccioli G, Peri F, Nervetti A, Ambanelli U, Savi M, Toxicity due to remission inducing drugs in rheumatoid arthritis. Association with HLA-B35 and Cw4 antigens, J Rheumatol. 1986; 13(1):65-8.
http://www.ncbi.nlm.nih.gov/pubmed/3084782
14. Ferraccioli GF, Peri F, Nervetti A, Mercadanti M, Cavalieri F, Dall'Aglio PP, Savi M, Ferrari C, Tiopronin-nephropathy: clinical, pathological, immunological and immunogenetic characteristics, Clin Exp Rheumatol. 1986; 4(1):9-15.
http://www.ncbi.nlm.nih.gov/pubmed/3516496
15. Ferraccioli GF, Cavalieri F, Mercadanti M, Salaffi F, Ambanelli U, Savi M, Association between DR3 and thrombocytopenia due to gold or tiopronin. Case reports and review of the literature, Clin Exp Rheumatol. 1985; 3(4):341-3.
http://www.ncbi.nlm.nih.gov/pubmed/3910323
16. Falezza GC, Corrocher R, Olivieri O, Capra F, Trevisoi E, Pennacchioni A, De Sandre G., In vitro production of PNH-like red blood cells by 2mercaptopropionylglycine, Acta Haematol. 1980; 64(6):310-4.
http://dx.doi.org/10.1159/000207309
17. 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.
http://dx.doi.org/10.1002/em.10035
18. Rao MV, Thiola induced effects on rat epididymal spermatozoa, Current Science 1986; 55(7), 378-380.
http://www.currentscience.ac.in/Downloads/article_id_055_07_0378_0380_0.pdf
19. Sany J, Combe B, Verdie-Petibon D, Tagemouati A, Daures JP, Long-term tolerability of tiopronin (Acadione) in the treatment of rheumatoid arthritis. Apropos of 140 personal cases, Rev Rhum Mal Osteoartic. 1990; 57(2):105-11.
http://www.ncbi.nlm.nih.gov/pubmed/2138812
20. Lindell A, Denneberg T, Eneström S, Fich C, Skogh T, Membranous glomerulonephritis induced by 2-mercaptopropionylglycine (2-MPG), Clin Nephrol. 1990; 34(3):108-15.
http://www.ncbi.nlm.nih.gov/pubmed/2225561
21. Ruocco V, de Angelis E, Lombardi ML, Pisani M, In vitro acantholysis by captopril and thiopronine, Dermatologica. 1988; 176(3):115-23.
http://dx.doi.org/10.1159/000248686
22. Cacoub P, Sbaď A, Azizi P, Gatfosse M, Godeau P, Piette JC, Polymyositis induced by tiopronine, Presse Med. 1999;28(17):911-2.
http://www.ncbi.nlm.nih.gov/pubmed/10360187
23. Bonnet M, Angibaud G, Cantagrel A, Montastruc JL, Clanet M, Myasthenia induced by tiopronin in the treatment of rheumatoid arthritis, Rev Neurol (Paris). 1995; 151(1):67-8.
http://www.ncbi.nlm.nih.gov/pubmed/7676135
24. 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.
http://dx.doi.org/10.3109/02841867709133944
25. Semenzato G, Pezzutto A, Amadori G, Raimondi R, Gasparotto G, alpha-Mercaptopropionyl-glycine influence on the in vitro proliferative response of human lymphocytes, Experientia. 1979; 35(8):1109-10.
http://www.ncbi.nlm.nih.gov/pubmed/477897
26. Dubini F, Sezzano P, Berti MA, Coppi G., Mutagenicity studies on tiopronin, Arzneimittelforschung. 1986; 36(11):1601-4.
http://www.ncbi.nlm.nih.gov/pubmed/3545224
27. Chan JY, Stout DL, Becker FF, Protective role of thiols in carcinogen-induced DNA damage in rat liver, Carcinogenesis. 1986; 7(10):1621-4.
http://dx.doi.org/10.1093/carcin/7.10.1621
28. Rao MV, Chinoy NJ, Shah VC, Thiola induced effects on reproductive organ morphology and fertility of male rats, Folia Biol (Krakow). 1987; 35(1-2):105-10.
http://www.new1.dli.ernet.in/data1/upload/insa/INSA_2/20005a13_643.pdf
29. Tiopronin, Individual drug monographs, 2014 by Mosby, Inc., an imprint of Elsevier Inc.
http://www.mosbydrugref.com/pdfs/c0019_Tiopronin_proof.pdf
30. Akrivis C, Vezyraki P, Kiortsis DN, Fotopoulos A, Evangelou A, Inhibition of puerperal lactation with 2-mercaptopropionyl-glycine, Eur J Clin Pharmacol. 2000; 56(9-10):621-3.
http://dx.doi.org/10.1007/s002280000228