Antioxidant effect of dipyridamole and its derivative RA-25 in mitochondria: correlation of activity and location in the membrane

Dipyridamole (DIP), a coronary vasodilator, presents coactivator activity f or a number of antitumor drugs as well as antioxidant activity in membrane systems. DIP and derivatives interact with membrane systems such as micelle s, phospholipid monolayers and vesicles. The antioxidant effect of DIP and several derivatives upon iron-induced lipoperoxidation on mitochondria has been reported and a good correlation between the hydrophobicity and their p rotective effect was found (M.F. Nepomuceno et al., Free Radic. Biol. Med., 23 (1997) 1046-1054). In the present work an effort is made to better unde rstand the role of DIP as inhibitor of Fe2+-induced lipid peroxidation in m itochondria. At low concentration, no significant effect on either state IV or state III respiration was found, discarding a possible direct interacti on of DIP or RA-25 with the peripheral benzodiazepine receptor. The associa tion constants for DIP and RA-25 in mitochondria were estimated, being 0.7 (mg/ml)(-1) for DIP and 0.2 (mg/ml)(-1) for RA-25. Oxygen consumption studi es in the presence of FeSO4 showed that the antioxidant effect of DIP or RA -25 did not involved the initial step of Fe2+ oxidation. Our data strongly support the hypothesis that the antioxidant effect of both DIP and RA-25 is related to their partition in the lipid phase of the mitochondrial membran e and not to a specific interaction with membrane proteins. This protection may be due either to a direct inhibition of the propagation steps or a sca venger effect on the radicular species that would trigger the peroxidative process. (C) 1999 Elsevier Science B.V. All rights reserved.