title: The control of hyperhomocysteinemia through thiol exchange mechanisms by mesna.
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.
authors: Pharmacology Unit, Department of Neuroscience, University of Siena, 53100, Siena, Italy.
authors: Danila
authors: D
authors: Di Giuseppe
authors: Raffaella
authors: R
authors: Priora
authors: Lucia
authors: L
authors: Coppo
authors: Monica
authors: M
authors: Ulivelli
authors: Sabina
authors: S
authors: Bartalini
authors: Domenico
authors: D
authors: Summa
authors: Antonios
authors: A
authors: Margaritis
authors: Simona
authors: S
authors: Frosali
authors: Paolo
authors: P
authors: Di Simplicio
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000188:drug therapy*; D008297:Male; D015080:Mesna / Q000494:pharmacology* / Q000627:therapeutic use; D008715:Methionine / Q000097:blood; D008875:Middle Aged; D010084:Oxidation-Reduction
chemical_list: D000975:Antioxidants; D006710:Homocysteine; D008715:Methionine; D015080:Mesna