Elevation of glutathione level in rat hepatocytes by hepatocyte growth factor via induction of gamma-glutamylcysteine synthetase.

Hepatocyte growth factor (HGF) was found to cause a dose- and time-dependent increase in intracellular glutathione (GSH) level (2. 0-fold in 24 h with 5 ng/ml) in rat hepatocytes. The activity of gamma-glutamylcysteine synthetase (gamma-GCS), the rate-limiting enzyme of GSH biosynthesis, was also increased by HGF (1.7-fold in 24 h with 5 ng/ml). Northern blot analysis revealed the induction of gamma-GCS mRNA. These increases by HGF were synergically stimulated by the addition of insulin. In contrast, epidermal growth factor had no effect on GSH level and gamma-GCS activity in hepatocytes. These results suggested that the induction of GSH synthesis by HGF is associated with the transcriptional activation of the gamma-GCS gene and the subsequent elevation of gamma-GCS activity.