Inhibition of Fe2+- and Fe3+- induced hydroxyl radical production by the iron-chelating drug deferiprone

• Published in: Free radical biology & medicine 2015-01, Vol.78, p.118-122
• Main Authors: Timoshnikov, V.A., Kobzeva, T.V., Polyakov, N.E., Kontoghiorghes, G.J.
• Format: Article
• Language: English
• Subjects: Deferiprone; EPR; Fenton reaction; Free radicals; Hydroxyl radical; Iron chelation; Photo-Fenton reaction; Phototoxicity; Spin traps
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.10.513

Deferiprone (L1) is an effective iron-chelating drug that is widely used for the treatment of iron-overload diseases. It is known that in aqueous solutions Fe2+ and Fe3+ ions can produce hydroxyl radicals via Fenton and photo-Fenton reactions. Although previous studies with Fe2+ have reported ferroxidase activity by L1 followed by the formation of Fe3+ chelate complexes and potential inhibition of Fenton reaction, no detailed data are available on the molecular antioxidant mechanisms involved. Similarly, in vitro studies have also shown that L1–Fe3+ complexes exhibit intense absorption bands up to 800nm and might be potential sources of phototoxicity. In this study we have applied an EPR spin trapping technique to answer two questions: (1) does L1 inhibit the Fenton reaction catalyzed by Fe2+ and Fe3+ ions and (2) does UV–Vis irradiation of the L1–Fe3+ complex result in the formation of reactive oxygen species. PBN and TMIO spin traps were used for detection of oxygen free radicals, and TEMP was used to trap singlet oxygen if it was formed via energy transfer from L1 in the triplet excited state. It was demonstrated that irradiation of Fe3+ aqua complexes by UV and visible light in the presence of spin traps results in the appearance of an EPR signal of the OH spin adduct (TMIO–OH, a(N)=14.15G, a(H)=16.25G; PBN–OH, a(N)=16.0G, a(H)=2.7G). The presence of L1 completely inhibited the OH radical production. The mechanism of OH spin adduct formation was confirmed by the detection of methyl radicals in the presence of dimethyl sulfoxide. No formation of singlet oxygen was detected under irradiation of L1 or its iron complexes. Furthermore, the interaction of L1 with Fe2+ ions completely inhibited hydroxyl radical production in the presence of hydrogen peroxide. These findings confirm an antioxidant targeting potential of L1 in diseases related to oxidative damage. [Display omitted] •The iron-chelating drug deferiprone (L1) inhibits the Fenton reaction catalyzed by Fe2+ and Fe3+ ions.•Interaction of L1 with Fe2+ ions results in formation of redox-inactive Fe3+ chelate complexes.•L1 completely inhibited OH radical production during light irradiation of iron aqua complexes.•No formation of singlet oxygen or free oxygen radicals was detected under irradiation of L1 or its iron complexes.