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The control of hyperhomocysteinemia through thiol exchange mechanisms by mesna

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Abstract

In hyperhomocysteinemic patients, after reaction with homocysteine-albumin mixed disulfides (HSS-ALB), mesna (MSH) forms the mixed disulfide with Hcy (HSSM) which can be removed by renal clearance, thus reducing the plasma concentration of total homocysteine (tHcy). In order to assess the HSS-ALB dethiolation via thiol exchange reactions, the distribution of redox species of cysteine, cysteinylglycine, homocysteine and glutathione was investigated in the plasma of healthy subjects: (i) in vitro, after addition of 35 μM reduced homocysteine (HSH) to plasma for 72 h, followed by MSH addition (at the concentration range 10–600 μM) for 25 min; (ii) in vivo, after oral treatment with methionine (methionine, 200 mg/kg body weight, observation time 2–6 h). In both experiments the distribution of redox species, but not the total amount of each thiol, was modified by thiol exchange reactions of albumin and cystine, with changes thermodynamically related to the pKa values of thiols in the corresponding mixed disulfides. MSH provoked a dose–response reversal of the redox state of aged plasma, and the thiol action was confirmed by in vivo experiments. Since it was observed that the dimesna production could be detrimental for the in vivo optimization of HSSM formation, we assume that the best plasma tHcy lowering can be obtained at MSH doses producing the minimum dimesna concentration in each individual.

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Abbreviations

Cys:

Cysteine

CysGly:

Cysteinylglycine

CSH:

Reduced Cys

CSSC:

Cystine

CSS-ALB:

Cysteine-albumin mixed disulfide

CGSH:

Reduced CysGly

CGSS:

CysGly disulfide

CGSS-ALB:

Cysteinylglycine-albumin mixed disulfide

DTNB:

5,5′-Dithiobis(2-nitrobenzoic acid)

CSSH:

Cysteine-homocysteine mixed disulfide

Hcy:

Homocysteine

HSH:

Reduced Hcy

HSSH:

Homocystine

HSS-ALB:

Homocysteine-albumin mixed disulfide

GSH:

Reduced glutathione

GSSG:

Glutathione disulfide

GSS-ALB:

Glutathione-albumin mixed disulfide

MLT:

Methionine loading test

MSH:

Mesna

MSSM:

Dimesna

MSS-ALB:

Mesna-albumin mixed disulfide

NEM:

N-ethylmaleimide

PSH:

Protein SH groups

TSH:

Total plasma thiols, sum of PSH and XSH

XSS-ALB:

Thiol-albumin mixed disulfides

tCSH, tGGSH, tHSH, tGSH:

Sum of concentrations of redox species expressed as reduced equivalents of XSH, namely XSSX = 2XSH

XSH and XSSX:

Thiols and disulfides of low molecular weight

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The authors have given their consent to be included in the present study.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Pharmacology Unit, Department of Neuroscience, University of Siena, 53100, Siena, Italy

    Danila Di Giuseppe, Raffaella Priora, Lucia Coppo, Monica Ulivelli, Sabina Bartalini, Domenico Summa, Antonios Margaritis, Simona Frosali & Paolo Di Simplicio

Authors
  1. Danila Di Giuseppe
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  2. Raffaella Priora
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  3. Lucia Coppo
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  4. Monica Ulivelli
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  5. Sabina Bartalini
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  6. Domenico Summa
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  7. Antonios Margaritis
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  8. Simona Frosali
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  9. Paolo Di Simplicio
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Corresponding author

Correspondence to Paolo Di Simplicio.

Additional information

D. Di Giuseppe and R. Priora equal experimental contribution.

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Di Giuseppe, D., Priora, R., Coppo, L. et al. The control of hyperhomocysteinemia through thiol exchange mechanisms by mesna. Amino Acids 46, 429–439 (2014). https://doi.org/10.1007/s00726-013-1636-4

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  • DOI: https://doi.org/10.1007/s00726-013-1636-4

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