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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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