LECITHINIZED SUPEROXIDE-DISMUTASE ENHANCES ITS PHARMACOLOGICAL POTENCY BY INCREASING ITS CELL-MEMBRANE AFFINITY

We performed the present study to clarify whether lecithinized superox ide dismutase (PC-SOD) enhanced its pharmacologic potency by increasin g its cell membrane affinity. PC-SOD, in which 4 molecules of a phosph atidylcholine (PC) derivative were covalently bound to each dimer of r ecombinant human CuZn-SOD (rhCuZn-SOD), was shown to have a high membr ane affinity using a laser confocal imaging technique. PC-SOD efficien tly scavenged superoxide anion (O-2(-)) produced by phorbol myristate acetate (PMA)-stimulated human neutrophils (IC50 0.60 U/ml), and it ex erted a dose-dependent scavenging effect (IC50 1.27 U/ml) even when th e neutrophils were washed after incubation with PC-SOD. In contrast, n either unmodified SOD nor polyethylene glycol-bound SOD (PEG-SOD) show ed a scavenging effect for washed neutrophils, even at a high concentr ation (100 U/ml). PC-SOD also showed a strong protective effect agains t human vascular endothelial cell damage caused by O-2(-) generated by stimulated neutrophils, and PC-SOD was approximately 100-fold more po tent than unmodified SOD (in vitro IC50 100 U/ml for PC-SOD and >10,00 0 U/ml for unmodified SOD). Moreover, PC-SOD (50,000 U/kg) had an inhi bitory effect on ischemia-reperfusion paw edema in mice, whereas neith er unmodified SOD nor PEG-SOD had any effect. These results suggest th at PC-SOD (designed to target for cell membranes) exerted a far higher pharmacologic activity by increasing cell membrane affinity than unmo dified SOD and may be potentially useful for various clinical applicat ions.