Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms

Methotrexate (MTX) is one of the most effective and widely used drugs in the management of autoimmune and dermatological diseases. Rheumatoid arthritis and psoriasis patients who are under long term MTX-therapy are at high risk of developing a liver injury. Accumulation of intracellular MTX-polyglutamate (MTX-PG), a metabolite of MTX triggers oxidative stress, inflammation, steatosis, fibrosis, and apoptosis in hepatocytes. MTX-PG causes oxidative stress in the liver by inducing lipid peroxidation thereby releasing reactive oxygen species and suppressing antioxidant response elements. MTX-PG induces several pro-inflammatory signaling pathways and cytokines such as tumor necrosis factor-alpha, nuclear factor kappa B and interleukin 6 (IL-6), IL-beta 1, IL-12. MTX-PG depletes hepatic folate level and decreases RNA and DNA synthesis leading to hepatocyte death. MTX-PG inhibits 5-aminoimidazole-4-carboxamide ribonucleotide transformylase enzyme and thereby causes accumulation of intracellular adenosine, which causes activation of hepatic stellate cells, extracellular matrix accumulation and hepatic fibrosis. MTX-PG induces hepatocytes apoptosis by activation of caspase 3 via the intrinsic pathway. Clinically, aggravation of underlying fatty liver to non-alcoholic steatohepatitis with fibrosis seems to be an important mechanism of liver injury in MTX-treated RA patients. Therefore, there is a need for monitoring liver injury in RA, psoriatic and cancer patients with NAFLD and fibrosis risk factors during MTX treatment. This review summarizes the possible molecular mechanism of MTX-induced hepatotoxicity. It may pave the way for early detection of liver injury and develop novel strategies for treating MTX mediated hepatotoxicity.