title: Reactions of captopril and epicaptopril with transition metal ions and hydroxyl radicals: an EPR spectroscopy study.
abstract: In the present study, using the technique of EPR spin trapping with DMPO a spin trap, we demonstrated formation of thiyl radicals from thiol-containing angiotensin converting enzyme (ACE) inhibitor captopril (CAP) and from its stereoisomer epicaptopril (EPICAP), a non-ACE inhibitor, in the process of .OH radical scavenging. Splitting constants of DMPO/thiyl radical adducts were identical for both thiols and were aN = 15.3 G, and aH = 16.2 G. Bimolecular rate constants for the reaction of CAP and EPICAP with .OH radicals were close to a diffusion-controlled rate (approximately 2 x 10(10) M-1s-1). Our data also show that both CAP and EPICAP reduce Fe(III) ions and that their respective thiyl radicals are formed in this reaction. In the presence of Fe(III), H2O2, and CAP, or EPICAP, .OH radicals were produced by a thiol-driven Fenton mechanism. Copper(II) ions were also reduced by these thiols, but no thiyl radicals could be detected in these reactions, and no .OH or other Fenton oxidants were observed in the presence of H2O2. Our data show direct evidence that thiol groups of CAP and EPICAP are involved in scavenging of .OH radicals. The direct .OH radical scavenging, together with the reductive "repair" of other sites of .OH radical attack, may contribute to the known protective effect of CAP against ischemia/reperfusion-induced arrhythmias. The formation of reactive thiyl radicals in the reactions of the studied compounds with .OH radicals and with Fe(III) ions may play a role in some of the known adverse effects of CAP.
authors.affiliation: Department of Medicine, George Washington University Medical Center, Washington, DC.
authors.forename: V
authors.initials: V
authors.lastname: Misík
authors.forename: I T
authors.initials: IT
authors.lastname: Mak
authors.forename: R E
authors.initials: RE
authors.lastname: Stafford
authors.forename: W B
authors.initials: WB
authors.lastname: Weglicki
mesh_terms: D002216:Captopril / Q000737:chemistry* / Q000494:pharmacology; D002412:Cations / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D003497:Cyclic N-Oxides; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers; D005609:Free Radicals; D017665:Hydroxyl Radical / Q000737:chemistry*; D066298:In Vitro Techniques; D007501:Iron / Q000737:chemistry; D008670:Metals / Q000737:chemistry*; D010084:Oxidation-Reduction; D013113:Spin Labels; D013237:Stereoisomerism
chemical_list: D002412:Cations; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D005609:Free Radicals; D008670:Metals; D013113:Spin Labels; D017665:Hydroxyl Radical; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D003300:Copper; D002216:Captopril; D007501:Iron