Increased biliary excretion of glutathione is generated by the glutathione-dependent hepatobiliary transport of antimony and bismuth

Gyurasics, Ágnes; Koszorús, László; Varga, F; Gregus, Zoltán

doi:10.1016/0006-2952(92)90526-o

Cited by 33 publications

(13 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such interactions could play an important role in the pharmacology of antimony. For example, it has been demonstrated that a glutathione-dependent hepatobiliary transport system exists for Sb(III) [18] in addition to increased cellular glutathione induced by Sb(III), although enzymes such as trypanothione reductase are thought to be the major target [19,20].In this work we used NMR spectroscopy and electrospray ionization (ESI)-MS to investigate the interaction between antimony tartrate and glutathione in aqueous solution and intact red blood cells. Sb(III)±GSH complexes are quite stable at physiological pH but weaken when pH is decreased.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interaction of antimony tartrate with the tripeptide glutathione

Sun

Yan

Cheng

2000

European Journal of Biochemistry

View full text Add to dashboard Cite

The tripeptide glutathione (g-l-Glu-l-Cys-Gly, GSH) is thought to play an important role in the biological processing of antimony drugs. We have studied the complexation of the antileishmanial drug potassium antimony(III) tartrate to GSH in both aqueous solution and intact red blood cells by NMR spectroscopy and electrospray ionization mass spectrometry. The deprotonated thiol group of the cysteine residue is shown to be the only binding site for Sb (III), and a complex with the stoichiometry [Sb(GS) 3 ] is formed. The stability constant for [Sb(GS) 3 ] was determined to be log K 25 (I 0.1 m, 298 K) based on a competition reaction between tartrate and GSH at different pH* values. In spite of being highly thermodynamically stable, the complex is kinetically labile. The rate of exchange of GSH between its free and Sb-bound form is pH-dependent, ranging from slow exchange on the 1 H-NMR timescale at low pH (2 s 21 at pH 3.2) to relatively rapid exchange at biological pH (. 440 s 21 ). Such facile exchange may be important in the transport of Sb(III) in various biofluids and tissues in vivo. Our spin±echo 1 H-NMR data show that Sb(III) rapidly entered red blood cell walls and was complexed by intracellular glutathione.Keywords: antimony; glutathione; nuclear magnetic resonance; red blood cells.Leishmaniasis is a parasitic infection caused by various species of the protozoan Leishmania. It remains one of the largest killers in the tropical regions of America, Africa and Asia, with approximately 1.5 billion people at risk and 20 million cases being reported annually. Among the drugs used to treat this condition, several antimony-containing complexes, such as N-methylglucamine antimonate(V) (Glucantimew), sodium stibogluconate (Pentostamw), sodium antimony(III) gluconate (Triostamw) and potassium antimony(III) tartrate (Tartar emeticw), are currently the first choice [1±3], despite their toxicity [4]. Antimony complexes with mannan appear to be promising for further improving the stability and solubility of these drugs [5]. Despite extensive clinical use for several decades, the molecular basis for the selective antileishmanial action of these drugs remains unclear. Furthermore, clinical resistance to these drugs has been increasingly reported in recent years [6±8]. It is generally believed that relatively nontoxic Sb(V) complexes may be prodrugs that could be reduced to the more toxic and active trivalent Sb(III) at or near the site of action (e.g. amastigotes) [9,10].Glutathione (g-l-Glu-l-Cys-Gly, GSH) is a potentially polydentate ligand, and is widely used as a model system for the binding of metal ions by peptides and proteins. It is present in many cells at millimolar concentration and generally is the most abundant nonprotein thiol. In cells, one of its roles is as a substrate for glutathione peroxidase, an enzyme capable of both removing hydrogen peroxide from cells and repairing peroxidatively damaged membranes. It is also involved in metal detoxification, and an ATP-dependent glutathione S-conjugate pump has ...

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

Interaction of antimony tartrate with the tripeptide glutathione

Sun

Yan

Cheng

2000

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…A relationship between antimony and GSH excretion in the bile has been shown, 23 and the transport of the metalloid as an unstable GSH complex was suggested. However, whether antimony methylation is altered by the GSH concentration has never been investigated.…”

Section: Influence Of Gsh Concentration In the Abiotic Methylation Ofmentioning

confidence: 99%

“…It has been demonstrated that a glutathione-dependent hepato biliary transport system exists for antimony(III). 23 The standard treatment of human leishmaniasis involves the use of pentavalent antimony compounds. The mode of action of these compounds has not been fully elucidated, but the possibility that antimony(III) is involved has been suggested.…”

Section: Introductionmentioning

confidence: 99%

Investigations into the role of methylcobalamin and glutathione for the methylation of antimony using isotopically enriched antimony(V)

Wehmeier

Raab

Feldmann

2004

Applied Organom Chemis

View full text Add to dashboard Cite

Glutathione (γ -Glu-Cys-Gly, GSH) and methylcobalamin (CH 3 -B 12 ) may play a role in the biomethylation process of antimony. To understand better the transformation of antimony in biological systems, we studied abiotic and biomethylation processes and the influence of GSH in the methylation.CH 3 -B 12 , acting as a possible methylating agent for antimony, was studied with GSH and in the absence of GSH. The most abundant product of this reaction was monomethylantimony, with a small concentration of the dimethylantimony species, as identified by hydride generation cryotrapping gas chromatography inductively coupled plasma mass spectrometry (HG-CT-GC-ICP-MS). In the same experiments we found that tris(γ -Glu-Cys-Gly)trithioantimonite [Sb(GS) 3 ] and di(γ -Glu-Cys-Gly)methyldithioantimonite [(CH 3 )Sb(GS)2] complexes were present using flowinjection electrospray ionization MS. Both complexes were also identified in a fermented sewage sample, suggesting that these complexes may play a role as intermediates in the biomethylation of antimony.However, CH 3 -B 12 is not the sole methylation agent, since it does not produce any trimethylantimony species as identified in anaerobic sewage sludge cultures inoculated with enriched 123 Sb(V). Species-specific 123/121 Sb isotope ratio measurements of the different methylantimony species suggest a stepwise methylation of antimony according to the Challenger mechanism.

show abstract

“…ESI-MS results show that Bi III binds to GSH with stoichiometries of Bi: GSH ¼ 1: 1, 1: 2 and 1: 3 [47], suggesting that thiolation of bismuth is likely to be the primary biochemical fate of bismuth drugs [48]. NMR studies show that Bi III forms a complex with GSH intracellularly and passes through the membrane of red blood cells slowly [49] and the transport of each Bi III ion results in the cotransport of three glutathione molecules [50]. Such an enhancement of intracellular bismuth uptake facilitated by thiolate ligands (e.g., GSH) may account for the high antimicrobial activities of bismuth thiolate complexes.…”

Section: Interaction Of Bismuth With Amino Acids and Peptidesmentioning

confidence: 99%