Liu K X, Kato Y, Kaku T I, Matsumoto K, Nakamura T, Sugiyama Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Am J Physiol. 1998 Jan;274(1):G21-8. doi: 10.1152/ajpgi.1998.274.1.G21.
The effect of protamine on the proliferative activity of hepatocyte growth factor (HGF) was examined in alpha-naphthyl isothiocyanate-intoxicated rats. Protamine pre-injection increased the hepatocyte labeling index induced by HGF four- to fivefold. A similar effect was also observed in partially hepatectomized rats. Because a cell surface heparin-like substance can bind to HGF and protamine has an affinity for heparin, protamine may affect HGF pharmacokinetics. In fact, protamine injection caused a transient increase in plasma HGF concentrations after administration of HGF and, in vitro, protamine eluted HGF prebound to heparin-Sepharose. Protamine also reduced the plasma clearance of HGF and increased 2.5-fold the exposure of hepatocytes to HGF in vivo. The enhancing effect of protamine on the mitogenic response of hepatocytes to HGF was also observed in vitro (approximately 2-fold after protamine pretreatment compared with HGF alone), suggesting that the enhancing effect of protamine on HGF-induced liver regeneration results from dual effects exerted by protamine 1) lowering the overall elimination of HGF and 2) directly stimulating hepatocyte mitosis induced by HGF.
在α-萘基异硫氰酸盐中毒的大鼠中检测了鱼精蛋白对肝细胞生长因子（HGF）增殖活性的影响。预先注射鱼精蛋白可使HGF诱导的肝细胞标记指数增加4至5倍。在部分肝切除的大鼠中也观察到了类似的效果。由于细胞表面的类肝素物质可与HGF结合，且鱼精蛋白对肝素有亲和力，因此鱼精蛋白可能会影响HGF的药代动力学。事实上，注射鱼精蛋白会导致在给予HGF后血浆HGF浓度短暂升高，并且在体外，鱼精蛋白可洗脱预先结合到肝素-琼脂糖上的HGF。鱼精蛋白还降低了HGF的血浆清除率，并使体内肝细胞对HGF 的暴露增加了2.5倍。在体外也观察到了鱼精蛋白对肝细胞对HGF有丝分裂反应的增强作用（与单独使用HGF相比，鱼精蛋白预处理后约增强2倍），这表明鱼精蛋白对HGF诱导的肝再生的增强作用源于鱼精蛋白发挥的双重作用：1）降低HGF的总体消除；2）直接刺激HGF诱导的肝细胞有丝分裂。
