The prooxidant properties of captopril.

The thiol drug captopril has been reported to possess reducing and transition metal-binding properties, which could result in specific changes in iron and copper prooxidant capacity. Thus, the effects of captopril on iron- and copper-induced oxidative injury were evaluated using deoxyribose as the oxidizable substrate in the presence of physiological phosphate concentrations but in the absence of the non-physiological chelator EDTA. In an iron(III)/H2O2/ascorbate oxidant system, captopril enhanced deoxyribose oxidation only when it was pre-mixed with iron, whereas it did not influence sugar degradation when not pre-mixed with the metal or when ascorbate was omitted. The physiological thiol GSH acted in a similar manner, whereas the SH-lacking angiotensin-converting enzyme inhibitor ramiprilat did not influence iron-induced deoxyribose oxidation, indicating that the thiol group is crucial in favouring enhanced iron reactivity due to 'malignant' chelation. Further specific experiments designed to evaluate possible thiol-dependent iron(III) reduction failed to demonstrate ferric to ferrous reduction by either captopril or reduced glutathione (GSH). When iron(III) was replaced by copper(II) to induce deoxyribose oxidation, captopril was prooxidant both in the presence and absence of ascorbate, and when pre-mixed or not with copper. On the other hand, GSH was prooxidant up to 2:1 molar ratio with respect to copper but markedly inhibited copper-dependent sugar oxidation beginning at molar ratio of 4:1. Ramiprilat did not significantly influence copper-induced deoxyribose oxidation. Moreover, unlike the experiments performed with iron, captopril, as well as GSH, readily reduced copper(II) to copper(I). Hence, captopril can act as prooxidant in the presence of iron or copper. In the former case, only 'malignant' iron chelation by the drug is involved in oxidant injury, whereas in the latter both copper chelation and reduction are operative, although specific chelating mechanisms are crucial in enhancing copper-induced oxidant injury. Captopril, therefore, cannot be considered simply as an 'antioxidant drug', and its catalytic transition metal-related prooxidant capacity should be taken into account in experimental and clinical investigations.