What is the mechanism of Methotrexate?

Methotrexate is a widely used medication in the treatment of various conditions, including some cancers, autoimmune diseases like rheumatoid arthritis, and psoriasis. Understanding the mechanism of methotrexate provides valuable insight into how this drug works at a molecular level, allowing for better clinical application and management of side effects.

Methotrexate is a folate antagonist. Folate, or vitamin B9, is essential for the synthesis of nucleotides, which are the building blocks of DNA and RNA. Methotrexate exerts its effects primarily by inhibiting the enzyme dihydrofolate reductase (DHFR). DHFR plays a crucial role in the conversion of dihydrofolate into tetrahydrofolate, a form of folate required for the synthesis of purines and thymidylate, which are necessary for DNA replication and cell division.

By inhibiting DHFR, methotrexate leads to a decrease in tetrahydrofolate levels, subsequently reducing the synthesis of DNA, RNA, and proteins. This inhibition affects rapidly dividing cells the most, such as those found in malignant tumors, the bone marrow, and the epithelium of the gastrointestinal tract. This property makes methotrexate an effective chemotherapeutic agent for treating certain types of cancer, such as leukemia, lymphomas, and osteosarcoma.

Apart from its role in cancer treatment, methotrexate is also utilized in managing autoimmune diseases. The precise mechanism by which methotrexate exerts its anti-inflammatory effects is not fully understood, but several pathways have been proposed. One significant pathway is the increase in extracellular levels of adenosine, a molecule with potent anti-inflammatory properties. Methotrexate inhibits enzymes involved in the breakdown of adenosine, leading to its accumulation. Elevated adenosine levels can suppress inflammation by binding to specific cell-surface receptors on immune cells, thereby reducing the production of pro-inflammatory cytokines.

Moreover, methotrexate is thought to induce apoptosis (programmed cell death) in activated T-cells, which are involved in the autoimmune response. By promoting apoptosis in these cells, methotrexate helps to decrease the aberrant immune activity that characterizes autoimmune diseases.

Additionally, methotrexate inhibits the enzyme aminoimidazole carboxamide ribonucleotide transformylase (AICAR transformylase), leading to the accumulation of AICAR, which subsequently inhibits the enzyme AMP-activated protein kinase (AMPK). Inhibition of AMPK affects various metabolic pathways and can contribute to the anti-inflammatory and immunosuppressive effects of methotrexate.

It is important to note that while methotrexate is effective in treating a range of conditions, it can also cause significant side effects due to its impact on rapidly dividing cells. Common side effects include bone marrow suppression, gastrointestinal disturbances, and hepatotoxicity. Therefore, patients on methotrexate require regular monitoring, including blood tests to check for toxicity and liver function.

In conclusion, methotrexate works through multiple mechanisms, primarily by inhibiting the enzyme dihydrofolate reductase, leading to reduced DNA synthesis, and by modulating immune function through pathways involving adenosine and AICAR. These actions make methotrexate a versatile drug in oncology and autoimmune disease management. Understanding these mechanisms allows clinicians to optimize its use and manage its side effects effectively.