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-α,
nuclear factor kappa B and
interleukin 6 (IL-6), IL- β1,
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.