Protective effect of infliximab on methotrexate-induced liver injury in rats: unexpected drug interaction

Area of Science:

• Hepatology
• Pharmacology
• Immunology

Background:

• Methotrexate (MTX) is a vital drug for cancer and inflammatory conditions.
• MTX's clinical use is limited by its significant hepatotoxic effects.
• Tumor necrosis factor-alpha (TNF-α) plays a role in inflammatory processes and liver injury.

Purpose of the Study:

• To investigate the potential protective effect of infliximab (INF), a TNF-α inhibitor, against MTX-induced hepatotoxicity.
• To evaluate the impact of combined MTX and INF administration on liver function and related biomarkers in a rat model.

Main Methods:

• Rats received single intraperitoneal injections of MTX (20 mg/kg), INF (7 mg/kg), or a combination (INF 72h prior to MTX).
• Liver damage was assessed histologically and by measuring TNF-α, nitric oxide (NO), arginase, and carbamoyl phosphate synthetase 1 (CPS-1) levels.
• Animals were observed for 5 days post-MTX administration.

Main Results:

• MTX significantly elevated TNF-α and NO levels compared to control, INF, and combined groups.
• Histological liver damage was greater in the MTX group than in the MTX + INF group.
• Arginase and CPS-1 were suppressed by MTX but increased in the MTX + INF group, while TNF-α was blocked.

Conclusions:

• Infliximab demonstrates partial protection against methotrexate-induced liver injury in rats.
• Combined MTX and INF therapy increases arginase and CPS-1 activity and blocks TNF-α.
• This combination may pose risks for cancer patients, potentially promoting tumor cell invasion and metastasis.