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.
Tsuboi
S
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Department of Biochemistry, Faculty of Pharmaceutical Science, Okayama University, Okayama, 700-8530, Japan. tsuboi@pheasant.pharm.okayama-u.ac.jp
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005721:Glutamate-Cysteine Ligase / Q000096:biosynthesis* / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation / Q000187:drug effects
D007328:Insulin; D012333:RNA, Messenger; D000082:Acetaminophen; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione