SYNTHESIS OF A SUPEROXIDE-DISMUTASE DERIVATIVE THAT CIRCULATES BOUND TO ALBUMIN AND ACCUMULATES IN TISSUES WHOSE PH IS DECREASED
SYNTHESIS OF A SUPEROXIDE-DISMUTASE DERIVATIVE THAT CIRCULATES BOUND TO ALBUMIN AND ACCUMULATES IN TISSUES WHOSE PH IS DECREASED
复制标题
DOI：
10.1021/bi00442a013
复制
发表时间：
1989-08-08
期刊：
影响因子：
2.9
通讯作者：
MORINO, Y
中科院分区：
文献类型：
--
作者：
INOUE, M;EBASHI, I;MORINO, Y
保护组织免受氧化应激是有氧生活的主要先决条件之一。由于静脉注射的Cu 2 +/Zn 2+型超氧化物歧化酶（SOD）从循环中消失，半衰期仅为5 min，因此其作为超氧化物自由基清除剂的临床应用受到限制。我们通过连接2摩尔疏水有机阴离子α-SOD合成了人红细胞型SOD衍生物（SM-SOD）。4-{[6-（N-马来酰亚胺基）己酰氧基甲基]枯基}半丁基酯化的聚（苯乙烯-共-马来酸）（SM）与二聚体酶的半胱氨酰残基结合而不降低酶活性。SM-SOD，但不是SOD，结合到白蛋白琼脂糖凝胶柱;结合的SM-SOD洗脱的缓冲溶液中含有0.5%的十二烷基硫酸钠或10 mM华法林，这表明SM-SOD可逆地结合到白蛋白上的华法林网站。由于SMI部分的两亲性质，SM-SOD也结合到细胞膜上，特别是当pH降低时。大鼠体内分析表明，静脉注射的SM-SOD循环结合在白蛋白中，半衰期为6小时。缺血后再灌注心律失常几乎完全防止单剂量的SM-SOD，但不是SOD。因此，SM-SOD在循环中的半衰期延长及其在pH降低的损伤部位的优先积累似乎是防止心肌损伤的原因。这些结果表明，超氧自由基和/或其代谢产物在缺血后再灌注心律失常的发病机制中发挥重要作用，SM-SOD可能有助于减轻缺血性心脏病的组织损伤。
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 in 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.