Methotrexate-induced apoptosis in hepatocytes after partial hepatectomy

Area of Science:

• Hepatology
• Molecular Biology
• Cell Death Research

Background:

• Hepatocyte apoptosis plays a critical role in liver injury and regeneration.
• Methotrexate is a chemotherapy agent with known hepatotoxicity.
• Understanding the mechanisms of drug-induced liver injury is crucial for patient safety.

Purpose of the Study:

• To investigate the role of methotrexate in inducing hepatocyte apoptosis in vivo.
• To elucidate the molecular pathways involved in methotrexate-induced liver cell death after partial hepatectomy.

Main Methods:

• Rats underwent partial hepatectomy followed by methotrexate injection.
• Apoptosis was assessed using terminal deoxynucleotidyl transferase-mediated nick end-labeling (TUNEL) and DNA gel electrophoresis.
• Key signaling molecules including JNK, AP-1, p53, and p21(WAF1/CIP1) were analyzed via Western blot and activity assays.

Main Results:

• Methotrexate induced characteristic DNA fragmentation and TUNEL-positive staining in hepatocytes post-hepatectomy.
• Methotrexate repressed the activity of c-Jun N-terminal kinase (JNK) and reduced c-Fos/c-Jun protein levels.
• A significant increase in p53 and subsequent upregulation of p21(WAF1/CIP1) protein levels were observed.

Conclusions:

• Partial hepatectomy combined with methotrexate triggers hepatocyte apoptosis.
• The observed apoptosis is mediated by the inhibition of the JNK-AP-1 pathway.
• Upregulation of the p53-p21(WAF1/CIP1) pathway is a key event in methotrexate-induced hepatocyte apoptosis.