An enzyme-linked immunosorbent assay was used to measure the level of hepatocyte growth factor in rat plasma at various times after two-thirds partial hepatectomy or CCl4 administration. An initial 17-fold rise and 13-fold rise in the level of hepatocyte growth factor was observed 2 hr after partial hepatectomy and CCl4 treatment, respectively, well before the onset of DNA synthesis in the liver. The peaks of DNA synthesis in remnant livers and livers exposed to CCl4 occurred at 24 hr and 48 hr, respectively, as determined by 5-bromo-2'-deoxyuridine labeling and [3H]thymidine uptake by the liver. A later peak level (17-fold above control) of hepatocyte growth factor at 24 hr after CCl4 treatment coincided with strong immunostaining of damaged or necrotic hepatocytes around central veins with an antibody to hepatocyte growth factor. This suggests a later intrahepatic origin of the signals for liver regeneration after hepatotoxic injury subsequent to the early extrahepatic production of hepatocyte growth factor at 2 hr after CCl4 administration. The absence of staining in the liver remnants in partially hepatectomized rats implies that the increase in hepatocyte growth factor seen in the plasma is caused by production at extrahepatic site(s). Possible sources include the pancreas, brain, thyroid and salivary glands, and Brunner's glands of the duodenum. Norepinephrine also increases in plasma as early as 2 hr after hepatectomy. In vitro, [3H]thymidine incorporation into hepatocyte DNA in the presence of hepatocyte growth factor is greater if 10(-5) mol/L norepinephrine is also present in the media.(ABSTRACT TRUNCATED AT 250 WORDS)