A mutant of deleted variant of hepatocyte growth factor (dHGF) with alanine substitution in the N-terminal basic region has higher activity in vivo

In a previous study, we generated a mutant of dHGF (deleted variant of hepa tocyte growth factor), termed #2, with higher specific activity than dHGF i n assays of mitogenic activity on rat hepatocytes and America opossum kidne y epithelial cells (OK). In the present study, we examine in vivo hepatotro pic and renotropic activities of #2 and its distribution to target tissues, liver and kidney. Administration of #2 to normal rats significantly increa sed serum levels of total protein, albumin, free-cholesterol, and HDL-chole sterol and liver weight in a dose-dependent manner. Analysis of these param eters suggests that #2 is more potent than dHGF as a hepatotropic factor in vivo. In addition, #2 reduced mortality of mercuric chloride-administered mice and the effect was stronger than that of dHGF. When injected to mice, a larger amount of #2 than dHGF was rapidly distributed to the liver. Sixty minutes after injection, the concentrations of #2 in plasma, liver, and ki dney were higher than those of dHGF. These distribution properties and the higher mitogenic activity in vitro may explain why #2 exerts more potent in vivo biological activity than dHGF. (C) 1999 Academic Press.