Mihara K, Sawai K, Takakura Y, Hashida M
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Biol Pharm Bull. 1994 Feb;17(2):296-301. doi: 10.1248/bpb.17.296.
The renal disposition characteristics of superoxide dismutase (SOD) and its derivatives, including macromolecular conjugates with polyethylene glycol and carboxymethyl-dextran, a cationized derivative, and glycosylated derivatives with galactose and mannose, were studied in the isolated perfused rat kidney. Renal disposition processes, such as glomerular filtration, tubular reabsorption, and uptake from the capillary side, were quantitatively determined by single-pass indicator dilution experiments under filtering and nonfiltering kidney conditions. Native SOD had a high glomerular filtration rate (40% of that of inulin) and was effectively reabsorbed in the tubules, while no significant uptake was observed from capillary side. Macromolecular conjugates showed restricted glomerular filtration due to an increase in molecular size. Cationization of SOD greatly enhanced its association with the tissue, not only from the luminal side but also from the capillary side, based upon electrostatic interaction. Galactosylated and mannosylated SOD showed reduced tubular reabsorption and increased exposure of the luminal surface to the enzyme. In addition, a small but significant uptake of mannosylated SOD from the capillary side was observed. This uptake was dose-dependent and completely inhibited by mannan, suggesting that mannose receptor-mediated endocytosis existed in the capillary side of the kidney. Thus, we can manipulate the renal disposition profiles of SOD by changing its physicochemical or biological properties through chemical modification.
在离体灌注大鼠肾脏中研究了超氧化物歧化酶（SOD）及其衍生物的肾脏处置特性，这些衍生物包括与聚乙二醇和羧甲基葡聚糖的大分子缀合物、一种阳离子化衍生物以及与半乳糖和甘露糖的糖基化衍生物。通过在滤过和非滤过肾脏条件下的单通道指示剂稀释实验，定量测定了肾小球滤过、肾小管重吸收以及从毛细血管侧摄取等肾脏处置过程。天然SOD具有较高的肾小球滤过率（为菊粉的40%），并在肾小管中被有效重吸收，而在毛细血管侧未观察到明显摄取。大分子缀合物由于分子大小增加而表现出受限的肾小球滤过。基于静电相互作用，SOD的阳离子化不仅从管腔侧而且从毛细血管侧极大地增强了其与组织的结合。半乳糖基化和甘露糖基化的SOD显示肾小管重吸收减少，管腔表面对该酶的暴露增加。此外，观察到甘露糖基化SOD从毛细血管侧有少量但显著的摄取。这种摄取是剂量依赖性的，并被甘露聚糖完全抑制，表明肾脏毛细血管侧存在甘露糖受体介导的内吞作用。因此，我们可以通过化学修饰改变SOD的物理化学或生物学性质来操纵其肾脏处置概况。
