THE PROOXIDANT PROPERTIES OF CAPTOPRIL

The thiol drug captopril has been reported to possess reducing and tra nsition metal-binding properties, which could result in specific chang es in iron and copper prooxidant capacity. Thus, the effects of captop ril on iron- and copper-induced oxidative injury were evaluated using deoxyribose as the oxidizable substrate in the presence of physiologic al phosphate concentrations but in the absence of the non-physiologica l chelator EDTA. In an iron (III)/H2O2/ascorbate oxidant system, capto pril enhanced deoxyribose oxidation only when it was pre-mixed with ir on, 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 angiorensin-conv erting enzyme inhibitor ramiprilat did not influence iron-induced deox yribose oxidation, indicating that the thiol group is crucial in favou ring enhanced iron reactivity due to 'malignant' chelation. Further sp ecific experiments designed to evaluate possible thiol-dependent iron( III) reduction failed to demonstrate ferric to ferrous reduction by ei ther captopril or reduced glutathione (GSH). When iron(III) was replac ed by copper(II) to induce deoxyribose oxidation, captopril was prooxi dant 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 a 2:1 molar ratio with respect to copper but markedly inhibited copper-depe ndent sugar oxidation beginning at molar ratio of 4:1. Ramiprilat did not significantly influence copper-induced deoxyribose oxidation. More over, unlike the experiments performed with iron, captopril, as well a s GSH, readily reduced copper(II) to copper(I). Hence, captopril can a ct as a prooxidant in the presence of iron or copper. In the former ca se, 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 enha ncing copper-induced oxidant injury. Captopril, therefore, cannot be c onsidered simply as an 'antioxidant drug', and its catalytic transitio n metal-related prooxidant capacity should be taken into account in ex perimental and clinical investigations.