Yabe Y, Nishikawa M, Tamada A, Takakura Y, Hashida M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
J Pharmacol Exp Ther. 1999 May;289(2):1176-84.
Four types of bovine liver catalase (CAT) derivatives, succinylated (Suc-CAT), galactosylated (Gal-CAT), mannosylated (Man-CAT), and polyethylene glycol conjugate (PEG-CAT), were synthesized and their pharmacokinetics and therapeutic potential in a hepatic ischemia/reperfusion injury model were studied in mice. About 90% of the CAT enzymatic activity was retained after chemical modification. Biodistribution studies showed that 111indium (111In)-Gal-CAT accumulated selectively in the liver parenchymal cells as 111In-CAT, whereas an increased amount of 111In-Suc-CAT and 111In-Man-CAT was delivered to liver nonparenchymal cells. 111In-PEG-CAT exhibited prolonged retention in plasma. Pharmacokinetic analysis revealed that the hepatic uptake clearances of 111In-Suc-CAT, 111In-Gal-CAT, and 111In-Man-CAT were much greater than that of 111In-CAT, whereas that of 111In-PEG-CAT was very small. In the ischemia/reperfusion injury model, in which hepatic injury was induced by occlusion of the portal vein for 30 min followed by 1 h reperfusion, the elevation of plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels was slightly inhibited by treatment with native CAT or Gal-CAT. PEG-CAT was less potent. In contrast, Suc-CAT and Man-CAT effectively suppressed the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase. Coinjection of mannosylated superoxide dismutase marginally improved the inhibitory effects of CAT derivatives. These results demonstrate that targeted CAT delivery to liver nonparenchymal cells via chemical modification is a promising approach to prevent hepatic injuries caused by reactive oxygen species. The potential usefulness of combining of CAT and superoxide dismutase derivatives is also demonstrated.
合成了四种牛肝过氧化氢酶（CAT）衍生物，琥珀酰化（Suc-CAT）、半乳糖基化（Gal-CAT）、甘露糖基化（Man-CAT）和聚乙二醇共轭物（PEG-CAT），并在小鼠肝缺血/再灌注损伤模型中研究了它们的药代动力学和治疗潜力。化学修饰后保留了约90%的CAT酶活性。生物分布研究表明，111铟（111In）-Gal-CAT像111In-CAT一样选择性地在肝实质细胞中蓄积，而111In-Suc-CAT和111In-Man-CAT递送至肝非实质细胞的量增加。111In-PEG-CAT在血浆中保留时间延长。药代动力学分析显示，111In-Suc-CAT、111In-Gal-CAT和111In-Man-CAT的肝脏摄取清除率远高于111In-CAT，而111In-PEG-CAT的肝脏摄取清除率非常小。在门静脉闭塞30分钟后再灌注1小时诱导肝损伤的缺血/再灌注损伤模型中，天然CAT或Gal-CAT治疗可轻微抑制血浆谷丙转氨酶和谷草转氨酶水平的升高。PEG-CAT的效力较低。相反，Suc-CAT和Man-CAT有效抑制了血浆谷丙转氨酶和谷草转氨酶的升高。共注射甘露糖基化超氧化物歧化酶可略微改善CAT衍生物的抑制作用。这些结果表明，通过化学修饰将CAT靶向递送至肝非实质细胞是预防活性氧引起的肝损伤的一种有前景的方法。还证明了联合使用CAT和超氧化物歧化酶衍生物的潜在有用性。
