Chlorite-hemoprotein interaction as key role for the pharmacological activity of the chlorite-based drug WF10

WF10 is a chlorite-based drug that modulates macrophages functional states and can be safely administered to humans. WF10 potentially modulates diseas e-related up-regulation of immune responses both in vitro and in vivo. Thus immune response is Influenced In a way that inappropriate Inflammatory rea ctions are downregulated. The molecular mechanisms involved are not complet ely understood. Biochemical data suggest the reaction of chlorite with hemo proteins as the central step in the activation process of the drug. Thereby a chlorinating agent is generated, resulting in the oxidation of reduced s ulfur-containing molecules and in the conversion of amino residues into mor e or less stable chloramines. The most prominent chloramine in vivo is taur ine chloramine. Taurine chloramine is a long-lived molecule with immunomodu latory properties. For instance, taurine chloramine inhibits the generation of macrophage inflammatory mediators such as nitric oxide, prostaglandin E -2 (PGE(2)), tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL- 6). This study on the biochemical mechanism of WF10 gives evidence that hem oprotein dependent chlorination of taurine is not only observed in vitro bu t also very likely in vivo. To characterize the oxidant, generated during h eme activation, different methods were used: Chemiluminescence, EPR-spectro scopy, UV/VIS-spectroscopy, gas (GC) and size exclusion chromatography. In summary, the results indicate as the first products of hemoprotein catalyze d chlorite activation a chloroxygen-species (probably HOCl/OCl) and a ferry l-oxygen species at the hemoprotein active site in analogy to the known per oxidase (compound I and II) intermediates. Moreover, hydrogen peroxide and chlorite seem to react in a similar way with heme centers. It is proposed t hat WF10 represents an "inactive" transport form of potentially active chlo rine. Reactivity of the latter is restricted unless heme moieties in protei ns or enzymes activate the "transport form" to perform reactions in analogy to peroxidases (i.e. myeloperoxidase-catalyzed formation of HOCl/OCl-).