Reversibility of disulfide formation. Comparison of chemical and enzyme-mediated reduction of penicillamine and captopril disulfides.
The reduction of penicillamine disulfide by reductants in aqueous solutions has been studied and compared with that for captopril disulfide. Whereas near quantitative reduction for captopril disulfide was achieved with tributyl phosphine (200 mM), no detectable penicillamine was formed from penicillamine disulfide. Thiol reductants (25 mM) were, however, partially able to reduce penicillamine disulfide with the most effective agent being glutathione (15% reduction) following by dithioerythritol (8%) and cysteine (5.1%). The reduction of penicillamine-cysteine disulfide by glutathione was 6-fold higher than for penicillamine disulfide. Kinetic analysis showed that the initial rate of reduction and equilibrium constant for the reduction of penicillamine disulfides by glutathione were 267- and 875-fold less than for captopril disulfide at pH 7.4. Biotransformation studies in the cytosol fraction of rat blood cells demonstrated that whereas 48% of the reduction of captopril disulfide was enzyme-mediated only 19% of the penicillamine formed was enzyme-mediated for penicillamine disulfide. Accumulation of disulfides of penicillamine in patients taking penicillamine may therefore be a problem during chronic therapy.
Drummer
O H
OH
Routley
L
L
Christophidis
N
N
D000818:Animals; D001711:Biotransformation; D002216:Captopril / Q000378:metabolism*; D004220:Disulfides / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D010084:Oxidation-Reduction; D010396:Penicillamine / Q000378:metabolism*; D051381:Rats
D004220:Disulfides; D002216:Captopril; D005978:Glutathione; D010396:Penicillamine