title: Synthesis of a superoxide dismutase derivative that circulates bound to albumin and accumulates in tissues whose pH is decreased.
abstract: Protection of tissues from oxidative stress is one of the major prerequisites for aerobic life. Since intravenously injected Cu2+/Zn2+-type superoxide dismutase (SOD) disappears from the circulation with a short half-life of 5 min, its clinical use as a scavenger for superoxide radical is limited. We synthesized a human erythrocyte type SOD derivative (SM-SOD) by linking 2 mol of hydrophobic organic anion, alpha-4-[( 6-(N-maleimido)hexanoyloxymethyl]cumyl]half-butyl-esterified poly(styrene-co-maleic acid) (SM), to the cysteinyl residues of the dimeric enzyme without decreasing enzymic activity. SM-SOD, but not SOD, bound to an albumin-Sepharose column; the bound SM-SOD was eluted by a buffer solution containing 0.5% sodium dodecyl sulfate or 10 mM warfarin, suggesting that SM-SOD reversibly binds to the warfarin site on albumin. Due to the amphipathic nature of the SMI moiety, SM-SOD bound also to cell membranes particularly when the pH was decreased. In vivo analysis in the rat revealed that intravenously injected SM-SOD circulated bound to albumin with a half-life of 6 h. Postischemic reperfusion arrhythmias were almost completely prevented by a single dose of SM-SOD, but not SOD. Thus, the prolonged half-life of SM-SOD in the circulation and its preferential accumulation in an injured site with decreased pH appeared to be responsible for preventing myocardial injury. These results suggest that superoxide radical and/or its metabolite(s) would play an important role in the pathogenesis of postischemic reperfusion arrhythmias and that SM-SOD may be useful for decreasing tissue injury in ischemic heart disease.
authors: Department of Biochemistry, Kumamoto University Medical School, Japan.
authors: M
authors: M
authors: Inoue
authors: I
authors: I
authors: Ebashi
authors: N
authors: N
authors: Watanabe
authors: Y
authors: Y
authors: Morino
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D003432:Cross-Linking Reagents; D004912:Erythrocytes / Q000201:enzymology; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008301:Maleimides; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D011137:Polystyrenes; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism; D013482:Superoxide Dismutase / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D003432:Cross-Linking Reagents; D008301:Maleimides; D011137:Polystyrenes; D012709:Serum Albumin; D013482:Superoxide Dismutase