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Am J Physiol Gastrointest Liver Physiol 274: G21-G28, 1998;
0193-1857/98 $5.00
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Vol. 274, Issue 1, G21-G28, January 1998

Protamine enhances the proliferative activity of hepatocyte growth factor in rats

Ke-Xin Liu1, Yukio Kato1, Tai-Ichi Kaku2, Kunio Matsumoto3, Toshikazu Nakamura3, and Yuichi Sugiyama1

1 Faculty of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113; 2 Bioproducts Industry Company, Ltd., Tomigaya, Shibuya-ku, Tokyo 151; and 3 Biomedical Research Center, Osaka University School of Medicine, Suita, Osaka 565, Japan

The effect of protamine on the proliferative activity of hepatocyte growth factor (HGF) was examined in alpha -naphthyl isothiocyanate-intoxicated rats. Protamine preinjection 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 (~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.

liver regeneration; liver function; drug delivery system


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