All Title Author
Keywords Abstract

PLOS ONE  2013 

Role of Efflux Pumps and Intracellular Thiols in Natural Antimony Resistant Isolates of Leishmania donovani

DOI: 10.1371/journal.pone.0074862

Full-Text   Cite this paper   Add to My Lib

Abstract:

Background In view of the recent upsurge in the phenomenon of therapeutic failure, drug resistance in Leishmania, developed under natural field conditions, has become a great concern yet little understood. Accordingly, the study of determinants of antimony resistance is urgently warranted. Efflux transporters have been reported in Leishmania but their role in clinical resistance is still unknown. The present study was designed to elucidate the mechanism of natural antimony resistance in L. donovani field isolates by analyzing the functionality of efflux pump(s) and expression profiles of known genes involved in transport and thiol based redox metabolism Methodology/Principal Findings We selected 7 clinical isolates (2 sensitive and 5 resistant) in addition to laboratory sensitive reference and SbIII resistant mutant strains for the present study. Functional characterization using flow cytometry identified efflux pumps that transported substrates of both P-gp and MRPA and were inhibited by the calmodulin antagonist trifluoperazine. For the first time, verapamil sensitive efflux pumps for rhodamine 123 were observed in L. donovani that were differentially active in resistant isolates. RT-PCR confirmed the over-expression of MRPA in isolates with high resistance index only. Resistant isolates also exhibited consistent down regulation of AQP1 and elevated intracellular thiol levels which were accompanied with increased expression of ODC and TR genes. Interestingly, γ-GCS is not implicated in clinical resistance in L. donovani isolates. Conclusions/Significance Here we demonstrate for the first time, the role of P-gp type plasma membrane efflux transporter(s) in antimony resistance in L. donovani field isolates. Further, decreased levels of AQP1 and elevated thiols levels have emerged as biomarkers for clinical resistance.

References

[1]  World Health Organization (1990) Control of the Leishmaniases. Report of a WHO Expert Committee. WHO Tech Rep Ser 793: 1–158.
[2]  Yamey G, Torreele E (2002) The world’s most neglected diseases [editorial] BMJ 325: 176–177 doi:10.1136/bmj.325.7357.176. PubMed: 12142292.
[3]  Alvar J, Yactayo S, Bern C (2006) Leishmaniasis and poverty. Trends Parasitol 22: 552–557. doi:10.1016/j.pt.2006.09.004. PubMed: 17023215.
[4]  Kedzierski L, Sakthianandeswaren A, Curtis JM, Andrews PC, Junk PC et al. (2009) Leishmaniasis: current treatment and prospects for new drugs and vaccines. Curr Med Chem 16: 599-614. doi:10.2174/092986709787458489. PubMed: 19199925.
[5]  Sundar S (2001) Drug resistance in Indian visceral Leishmaniasis. Trop Med Int Health 6: 849–854. doi:10.1046/j.1365-3156.2001.00778.x. PubMed: 11703838.
[6]  Hadighi R,?Mohebali M,?Boucher P,?Hajjaran H,?Khamesipour A?et al. (2006) Unresponsiveness to Glucantime treatment in Iranian cutaneous Leishmaniasis due to drug-resistant Leishmania tropica parasites. PLOS Med 3: e162. doi:10.1371/journal.pmed.0030162. PubMed: 16605301.
[7]  Rojas R, Valderrama L, Valderrama M, Varona MX, Ouellette M et al. (2006) Resistance to antimony and treatment failure in human?Leishmania?(Viannia) infection. J Infect Dis?193: 1375-1383. doi:10.1086/503371. PubMed: 16619185.
[8]  Yardley V, Ortuno N, Llanos-Cuentas A, Chappuis F, Doncker SD et al. (2006) American tegumentary Leishmaniasis: Is antimonial treatment outcome related to parasite drug J Infect Dis 194: 1168-1175. doi:10.1086/507710. PubMed: 16991093.
[9]  Abdo MG,?Elamin WM,?Khalil EA,?Mukhtar MM (2003) Antimony-resistant Leishmania donovani in eastern Sudan: incidence and in vitro correlation. East Mediterr Health J?9: 837-843. PubMed: 15748080.
[10]  Croft SL, Sundar S, Fairlamb AH (2006) Drug resistance in Leishmaniasis. Clin Microbiol Rev 19: 111–126. doi:10.1590/S1415-52732006000100012. PubMed: 16418526.
[11]  Sundar S, Murray HW (2005) Availability of miltefosine for the treatment of kala-azar in India. Bull World Health Organ 83: 394-395. PubMed: 15976883.
[12]  World Health Organization (2006) Control of Leishmaniasis. Report by the Secretariat. Geneva, Switzerland: World Health Organization. . Accessed 2013 August 14.
[13]  Ouellette M, Drummelsmith J, Papadopoulou B (2004) Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist Update 7: 257–266. doi:10.1016/j.drup.2004.07.002. PubMed: 15533763.
[14]  Marquis N, Gourbal B, Rosen BP, Mukhopadhyay R, Ouellette M (2005) Modulation of aquaglyceroporin AQP1 gene transcript levels in drug-resistant Leishmania. Mol Microbiol 57: 1690-1699. doi:10.1111/j.1365-2958.2005.04782.x. PubMed: 16135234.
[15]  Légaré D, Richard D, Mukhopadhyay R, Stierhof YD, Rosen BP et al. (2001) The Leishmania ATP-binding casstte protein P-GPA is an intracellular metal–thiol transporter ATPase. J Biol Chem 276: 26301–26307. doi:10.1074/jbc.M102351200. PubMed: 11306588.
[16]  Ouellette MLe′ gare′ D, Haimeur A, Grondin K, Roy G et al (1998) ABC transporters in Leishmania and their role in drug resistance. Drug Resist Update 1: 43–48. doi:10.1016/S1368-7646(98)80213-6. PubMed: 17092795.
[17]  Mukhopadhyay R, Dey S, Xu N, Gage D, Lightbody J et al. (1996) Trypanothione overproduction and resistance to antimonials and arsenicals in Leishmania. Proc Natl Acad Sci U S A 93: 10383–10387. doi:10.1073/pnas.93.19.10383. PubMed: 8816809.
[18]  Ashutosh , Sundar S, Goyal N (2007) Molecular mechanisms of antimony resistance in Leishmania. J Med Microbiol 56: 143-153. doi:10.1099/jmm.0.46841-0. PubMed: 17244793.
[19]  Maharjan M, Singh S, Chatterjee M, Madhubala R (2008) Role of aquaglyceroporin (AQP1) gene and drug uptake in antimony-resistant clinical isolates of Leishmania donovani. Am J Trop Med Hyg 79: 69–75. PubMed: 18606765.
[20]  Decuypere S, Rijal S, Yardley V, De Doncker S, Laurent T et al. (2005) Gene Expression Analysis of the Mechanism of Natural Sb(V) Resistance in Leishmania donovani isolates from Nepal. Antimicrob Agents Chemother 49: 4616–4621. doi:10.1128/AAC.49.11.4616-4621.2005. PubMed: 16251303.
[21]  Decuypere S, Vanaerschot M, Rijal S, Yardley V, Maes L et al. (2008) Gene expression profiling of Leishmania (Leishmania) donovani: overcoming technical variation and exploiting biological variation. Parasitol 135: 1-12. PubMed: 17931458.
[22]  Torres DC, Adaui V, Ribeiro-Alves M, Romero GAS, Arévalo J et al. (2010) Targeted gene expression profiling in Leishmania braziliensis and Leishmania guyanensis parasites isolated from Brazilian patients with different antimonial treatment outcomes. Infect Genet Evol 10: 727-733. doi:10.1016/j.meegid.2010.05.006. PubMed: 20478409.
[23]  Adaui V, Castillo D, Zimic M, Gutierrez A, Decuypere S et al. (2011) Comparative gene expression analysis throughout the life cycle of Leishmania braziliensis: diversity of expression profiles among clinical isolates. Plos Neg Trop. Drosophila Inf Serv 5: e1021. doi:10.1371/journal.pntd.0001021.
[24]  Mittal MK, Rai S, Ashutosh Ravinder, Gupta S et al. (2007) Characterization of natural antimony resistance in Leishmania donovani isolates. Am J Trop Med Hyg 76: 681-688. PubMed: 17426170.
[25]  Mukherjee A, Padmanabhan PK, Singh S, Roy G, Girard I et al. (2007) Role of ABC transporter MRPA, γ-glutamylcysteine synthetase and ornithine decarboxylase in natural antimony-resistant isolates of Leishmania donovani. J Antimicrob Chemother 59: 204-211. PubMed: 17213267.
[26]  Mandal G, Sarkar A, Saha P, Singh N, Sundar S et al. (2009) Functionality of drug efflux pumps in antimonial resistant Leishmania donovani field isolates. Indian J Biochem Biophys 46: 86-92. PubMed: 19374259.
[27]  Chulay JD,?Bryceson AD (1983) Quantitation of amastigotes of Leishmania donovani in smears of splenic aspirates from patients with visceral leishmaniasis. Am J Trop Med Hyg 32(3): 475-479. PubMed: 6859397.
[28]  Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402-408. doi:10.1006/meth.2001.1262. PubMed: 11846609.
[29]  Sanchez A, Castanys S, Gamarro F (1994) Increased P-type ATPase activity in Leishmania tropica resistant to methotrexate. Biochem Biophys Res Commun 199: 855-861. doi:10.1006/bbrc.1994.1307. PubMed: 7907868.
[30]  Urbina JA, Vivas J, Ramos H, Larralde G, Aguilar Z et al. (1988) Alteration of lipid order profile and permeability of plasma membranes from Trypanosoma cruzi epimastigotes grown in the presence of ketoconazole. Mol Biochem Parasitol 30: 185-195. doi:10.1016/0166-6851(88)90111-9. PubMed: 2845268.
[31]  Cohen BE, Ramos H, Gamargo M, Urbina J (1986) The water and ionic permeability induced by polyene antibiotics across plasma membrane vesicles from Leishmania sp. Biochim Biophys Acta 860: 57-65. doi:10.1016/0005-2736(86)90498-0. PubMed: 3730386.
[32]  Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 582: 67-78. doi:10.1016/0304-4165(79)90289-7. PubMed: 760819.
[33]  Sarkar A, Mandal G, Singh N, Sundar S, Chatterjee M (2009) Flow cytometric determination of intracellular non-protein thiols in Leishmania promastigotes using 5-chloromethyl fluorescein diacetate. Exp Parasitol 122: 299–305. doi:10.1016/j.exppara.2009.04.012. PubMed: 19393240.
[34]  Seelig GF, Meister A (1985) Glutathione biosynthesis. gamma-glutamylcysteine synthetase from rat kidney. methods Enzymol 113: 379-390.
[35]  Hamilton CJ, Saravanamuthu A, Eggleston IM, Fairlamb AH (2003) Ellman’s-reagent-mediated regeneration of trypanothione in situ: substrate-economical microplate and time-dependent inhibition assays for trypanothione reductase. Biochem J 369: 529-537. doi:10.1042/BJ20021298. PubMed: 12416994.
[36]  Molnár J, Engi H, Hohmann J, Molnár P, Deli J et al. (2010) Reversal of multidrug resitance by natural substances from plants. Curr Top Med Chem 10: 1757-1768. doi:10.2174/156802610792928103. PubMed: 20645919.
[37]  Shapiro AB, Ling V (1998) The mechanism of ATP-dependent multidrug transport by P-glycoprotein. Acta Physiol Scand Suppl 643: 227-234. PubMed: 9789565.
[38]  Poot M, Kavanagh TJ, Kang HC, Haugland RP, Rabinovitch PS (1991) Flow cytometric analysis of cell cycle-dependent changes in cell thiol level by combining a new laser dye with Hoechst 33342. Cytometry 12: 184–187. doi:10.1002/cyto.990120214. PubMed: 1710962.
[39]  Haimeur A, Guimond C, Pilote S, Mukhopadhyay R, Rosen BP et al. (1999) Elevated levels of polyamines and trypanothione resulting from overexpression of the ornithine decarboxylase gene in arsenite-resistant Leishmania. Mol Microbiol 34: 726–735. doi:10.1046/j.1365-2958.1999.01634.x. PubMed: 10564512.
[40]  Grondin K, Haimeur A, Mukhopadhyay R, Rosen BP, Ouellette M (1997) Co-amplification of the γ-glutamylcysteine synthetase gene gsh1 and of the ABC transporter gene P-gpA in arsenite-resistant Leishmania tarentolae. EMBO J 16: 3057-3065. doi:10.1093/emboj/16.11.3057. PubMed: 9214623.
[41]  Cunningham ML, Fairlamb AH (1995) Trypanothione reductase from Leishmania donovani. Purification, characterisation and inhibition by trivalent antimonials. Eur J Biochem 230: 460-468. doi:10.1111/j.1432-1033.1995.tb20583.x. PubMed: 7607216.
[42]  Gourbal B, Sonuc N, Bhattacharjee H, Legare D, Sundar S et al. (2004) Drug uptake and modulation of drug resistance in Leishmania by an aquaglyceroporin. J Biol Chem 279: 31010–31017. doi:10.1074/jbc.M403959200. PubMed: 15138256.
[43]  Mandal S, Maharjan M, Singh S, Chatterjee M, Madhubala R (2010) Assessing aquaglyceroporin gene status and expression profile in antimony-susceptible and -resistant clinical isolates of Leishmania donovani from India. J Antimicrob Chemother 65: 496–507. doi:10.1093/jac/dkp468. PubMed: 20067981.
[44]  Homolya L, Váradi A, Sarkadi B (2003) Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate. Biofactors 17: 103-114. doi:10.1002/biof.5520170111. PubMed: 12897433.
[45]  Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of . Nat Rev Cancer 2: 48-58. doi:10.1038/nrc706. PubMed: 11902585.
[46]  Parodi-Talice A, Araújo JM, Torres C, Pérez-Victoria JM, Gamarro F et al. (2003) The overexpression of a new ABC transporter in Leishmania is related to phospholipid trafficking and reduced infectivity. Biochim Biophys Acta 1612: 195-207. doi:10.1016/S0005-2736(03)00131-7. PubMed: 12787938.
[47]  Araújo-Santos JM, Parodi-Talice A, Castanys S, Gamarro F (2005) The overexpression of an intracellular ABCA-like transporter alters phospholipid trafficking in Leishmania. Biochem Biophys Res Commun 330: 349-355. doi:10.1016/j.bbrc.2005.02.176. PubMed: 15781271.
[48]  Chiquero MJ, Pérez-Victoria JM, O’Valle F, González-Ros JM, del Moral RG et al. (1998) Altered drug membrane permeability in a . Biochem Pharmacol 55: 131-139. doi:10.1016/S0006-2952(97)00385-7. PubMed: 9448735.
[49]  Chow LM, Wong AK, Ullman B, Wirth DF (1993) Cloning and functional analysis of an extrachromosomally amplified multidrug resistance-like gene in Leishmania enriettii. Mol Biochem Parasitol 60: 195-208. doi:10.1016/0166-6851(93)90131-G. PubMed: 8232412.
[50]  Gueiros-Filho FJ, Viola JP, Gomes FC, Farina M, Lins U et al. (1995) Leishmania amazonensis: multidrug resistance in . Exp Parasitol 81: 480-490. doi:10.1006/expr.1995.1141. PubMed: 8542989.
[51]  Henderson DM, Sifri CD, Rodgers M, Wirth DF, Hendrickson N et al. (1992) Multidrug resistance in Leishmania donovani is conferred by amplification of a gene homologous to the mammalian mdr1 gene. Mol Cell Biol 12: 2855-2865. PubMed: 1350325.
[52]  Katakura K, Iwanami M, Ohtomo H, Fujise H, Hashiguchi Y (1999) Structural and functional analysis of the LaMDR1 multidrug resistance gene in Leishmania amazonensis. Biochem Biophys Res Commun 255: 289-294. doi:10.1006/bbrc.1999.0209. PubMed: 10049701.
[53]  Coelho AC, Beverley SM, Cotrim PC (2003) Functional genetic identification of PRP1, an ABC transporter superfamily member conferring pentamidine resistance in Leishmania major. Mol Biochem Parasitol 130: 83–90. doi:10.1016/S0166-6851(03)00162-2. PubMed: 12946844.
[54]  Leprohon P, Légaré D, Ouellette M (2009) Intracellular localization of the ABCC proteins of Leishmania and their role in resistance to antimonials. Antimicrob Agents Chemother 53: 2646–2649. doi:10.1128/AAC.01474-08. PubMed: 19307364.
[55]  Dey S, Ouellette M, Lightbody J, Papadopoulou B, Rosen BP (1996) An ATP-dependent As(III)-glutathione transport system in membrane vesicles of Leishmania tarentolae. Proc Natl Acad Sci U S A 93: 2192–2197. doi:10.1073/pnas.93.5.2192. PubMed: 8700907.
[56]  Sodré CL, Moreira BL, Nobrega FB, Gadelha FR, Meyer-Fernandes JR et al. (2000) Characterization of the intracellular Ca(2+) pools involved in the calcium homeostasis in Herpetomonas sp. promastigotes. Arch Biochem Biophys 380: 85-91. doi:10.1006/abbi.2000.1899. PubMed: 10900136.
[57]  Lizumi K, Mikami Y, Hshimoto M, Nara T, Hara Y et al. (2006) Molecular cloning and characterization of ouabain- insensitive Na+- ATPase in the parasitic protist, Trypanosoma cruzi. Biochim Biophys Acta 1978: 738-746.
[58]  Prasad V, Kaur J, Dey CS (2000) Arsenite resistant Leishmania donovani promastigotes express an enhanced membrane P-type adenosine triphosphatase activity that is sensitive to verapamil treatment. Parasitol Res 86: 661-664. doi:10.1007/PL00008548. PubMed: 10952266.
[59]  Singh N, Almeida R, Kothari H, Kumar P, Mandal G et al. (2007) Differential gene expression analysis in antimony-unresponsive Indian kala azar (visceral Leishmaniasis) clinical isolates by DNA microarray. Parasitol 134: 777–787. doi:10.1017/S0031182007002284. PubMed: 17306059.
[60]  Messaritakis I, Christodoulou V, Mazeris A, Koutala E, Vlahou A et al. (2013) Drug Resistance in natural isolates of Leishmania donovani promastigotes is dependent of Pgp170 expression. PLOS ONE 8: e65467. doi:10.1371/journal.pone.0065467. PubMed: 23776486.
[61]  Mary C, Faraut F, Deniau M, Dereure J, Aoun K et al. (2010) Frequency of drug resistance gene amplification in clinical?Leishmania?strains. Int J Microbiol 2010: Article ID 819060 (8 pages).
[62]  Neal RA, van Bueren J, McCoy NJ, Iwobi M (1989) Reversal of drug resistance in Trypanosoma cruzi and Leishmania donovani by verapamil. Trans R Soc Trop Med Hyg 83: 197-198. doi:10.1016/0035-9203(89)90642-1. PubMed: 2558433.
[63]  Valiathan R, Dubey ML, Mahajan RC, Malla N (2006) Leishmania donovani: effect of verapamil on in vitro susceptibility of promastigote and amastigote stages of Indian clinical isolates to sodium stibogluconate. Exp Parasitol 114: 103-108. doi:10.1016/j.exppara.2006.02.015. PubMed: 16616137.
[64]  Sharom FJ (2008) ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics J 9: 105-127. doi:10.2217/14622416.9.1.105. PubMed: 18154452.
[65]  Essoda?gui M, Frézard F, Moreira ES, Dagger F, Garnier-Suillerot AEssoda?¨gui M, Fre′zard F, Moreira ESA, Dagger F, Garnier-Suillerot A (1999) Energy-dependent efflux from Leishmania promastigotes of substrates of the mammalian multidrug resistance pumps. Mol Biochem Parasitol 100: 73-84. doi:10.1016/S0166-6851(99)00036-5. PubMed: 10376995.
[66]  Choudhuri S, Klaassen CD (2006) Structure, function, expression, genomic organization and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP) and ABCG (BCRP) efflux transporters. Int J Toxicol 25: 231-235. doi:10.1080/10915810600746023. PubMed: 16815813.
[67]  Leschziner GD, Andrew T, Pirmohamed M, Johnson MR (2007) ABCB1 genotype and P-GP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 7: 154-179. doi:10.1038/sj.tpj.6500413. PubMed: 16969364.
[68]  Sinha S, Sundaram S, Kumar V, Tripathi A (2011) Antimony resistance during visceral Leishmaniasis: a possible consequence of serial mutations in ABC transporters of Leishmania species Bioinformation 6: 107-110.
[69]  Basselin M, Denise H, Coombs GH, Barrett MP (2002) Resistance to pentamidine in Leishmania mexicana involves exclusion of the drug from the mitochondrion. Antimicrob Agents Chemother 46: 3731-3738. doi:10.1128/AAC.46.12.3731-3738.2002. PubMed: 12435669.
[70]  Mukherjee A, Padmanabhan PK, Sahani MH, Barrett MP, Madhubala R (2006) Roles for mitochondria in pentamidine susceptibility and resistance in Leishmania donovani. Mol Biochem Parasitol 145: 1-10. doi:10.1016/j.molbiopara.2005.08.016. PubMed: 16219371.
[71]  Hidaka H, Naito Y (1998) Inhibitor of calmodulin and calmodulin dependent enzyme. Tanpakushitsu Kakusan Koso 43: 1732-1738. PubMed: 9788175.
[72]  Benerjee C, Sarkar D, Bhaduri A (1999) Ca++ and calmodulin dependent protein phosphatise from Leishmania donovani. 118: 567-73.
[73]  Michiels J, Xi C, Verhaert J, Vanderleyden J (2002) The functions of Ca(2+) in bacteria: a role for EF-hand proteins? Trends Microbiol 10: 87-93. doi:10.1016/S0966-842X(01)02284-3. PubMed: 11827810.
[74]  Molnár J, Hevér A, Fakla I, Fischer J, Ocsovski I et al. (1997) Inhibition of the transport function of membrane proteins by some substituted phenothiazines in E. coli and multidrug resistant tumor cells. Anticancer Res 17: 481-486. PubMed: 9066699.
[75]  Kaatz GW, Moudgal VV, Seo SM, Kristiansen JE (2003) Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob Agents Chemother 47: 719-726. doi:10.1128/AAC.47.2.719-726.2003. PubMed: 12543683.
[76]  Hendricks O, Butterworth TS, Kristiansen JE (2003) The in vitro antimicrobial effect of non-antibiotics and putative inhibitors of efflux pumps on Pseudomonas aeruginosa and Staphylococcus aureus. Int J Antimicrob Agents 22: 262-264. doi:10.1016/S0924-8579(03)00205-X. PubMed: 13678831.
[77]  Haimeur A, Brochu C, Genest P, Papadopoulou B, Ouellette M (2000) Amplification of the ABC transporter gene P-GPA and increased trypanothione levels in potassium antimonyl tartrate (SbIII) resistant Leishmania tarentolae. Mol Biochem Parasitol 108: 131–135. doi:10.1016/S0166-6851(00)00187-0. PubMed: 10802326.
[78]  Mandal G, Wyllie S, Singh N, Sundar S, Fairlamb AH et al. (2007) Increased levels of thiols protect antimony unresponsive Leishmania donovani field isolates against reactive oxygen species generated by trivalent antimony. Parasitol 134: 1679–1687. PubMed: 17612420.
[79]  Ferreira Cdos S, Martins PS, Demicheli C, Brochu C, Ouellette M et al. (2003) Thiol-induced reduction of antimony (V) into antimony (III): a comparative study with trypanothione, cysteinyl-glycine, cysteine and glutathione. Biometals 16: 441–446. doi:10.1023/A:1022823605068. PubMed: 12680707.
[80]  Frézard F, Demicheli C, Ferreira CS, Costa MA (2001) Glutathione-induced conversion of pentavalent antimony to trivalent antimony in meglumine antimoniate. Antimicrob Agents Chemother 45: 913–916. doi:10.1128/AAC.45.3.913-916.2001. PubMed: 11181379.
[81]  Yan S, Li F, Ding K, Sun H (2003a) Reduction of pentavalent antimony by trypanothione and formation of a binary and ternary complex of antimony(III) and trypanothione. J Biol Inorg Chem JBIC Publ Society Of Biological Inorganic Chemistry 8: 689–697. doi:10.1007/s00775-003-0468-1.
[82]  Yan S, Wong IL, Chow LM, Sun H (2003b) Rapid reduction of pentavalent antimony by trypanothione: potential relevance to antimonial activation. Chem Commun (Camb) 2: 266–267. PubMed: 12585423.
[83]  Ariyanayagam MR, Fairlamb AH (2001) Ovothiol and trypanothione as antioxidants in trypanosomatids. Mol Biochem Parasitol 115: 189–198. doi:10.1016/S0166-6851(01)00285-7. PubMed: 11420105.
[84]  Légaré D, Papadopoulou B, Roy G, Mukhopadhyay R, Haimeur A et al. (1997) Efflux systems and increased trypanothione levels in arsenite resistant Leishmania. Exp Parasitol 87: 275-282. doi:10.1006/expr.1997.4222. PubMed: 9371094.
[85]  Leprohon P, Légaré D, Raymond F, Madore E, Hardiman G et al. (2009) Gene expression modulation is associated with gene amplification, supernumerary chromosomes and chromosome loss in antimony-resistant Leishmania infantum. Nucleic Acids Res 37: 1387–1399. doi:10.1093/nar/gkn1069. PubMed: 19129236.

Full-Text

comments powered by Disqus