Methotrexate is a medication prescribed for a wide range of health issues, from certain cancers to autoimmune diseases like rheumatoid arthritis and psoriasis. It belongs to a class of drugs known as antimetabolites. The drug’s function depends on the condition being treated, employing different biological pathways. For some conditions, it halts cell growth, while for others, it works by calming an overactive immune system.
Inhibition of Folate Metabolism
Folate, a B vitamin, is necessary for the synthesis of DNA and RNA. Before the body can use dietary folate, it must be converted into its active form, tetrahydrofolate. This activation process is carried out by an enzyme called dihydrofolate reductase (DHFR). Without DHFR, folate from food remains unusable for building new genetic material.
Methotrexate’s primary mechanism involves directly obstructing the DHFR enzyme. It is structurally similar to folic acid, allowing it to bind tightly to DHFR, blocking the enzyme’s active site. This action is like a key breaking off in a lock; the methotrexate molecule occupies the space intended for dihydrofolate, preventing the enzyme from performing its function. As a result, the production of active tetrahydrofolate ceases.
The consequence of DHFR inhibition is a shortage of the building blocks for DNA and RNA synthesis. Cells are deprived of the necessary components—purines and thymidylate—to replicate their genetic code and divide. This disruption of DNA production is the most direct biochemical effect of the drug, setting off a cascade of consequences for cells throughout the body.
Effects on Rapidly Dividing Cells
The halt in DNA synthesis caused by methotrexate disproportionately affects cells that are in a state of rapid proliferation. Cancer cells, defined by uncontrolled and swift division, are particularly susceptible to this mechanism. Their constant need for new DNA means a shortage of genetic building blocks can stop tumor progression, which is why methotrexate is used as a chemotherapeutic agent.
This mechanism also impacts healthy cells in the body that have a high turnover rate. These include cells in the bone marrow, hair follicles, and the lining of the gastrointestinal tract. The effect on these healthy cells leads to common side effects like bone marrow suppression, hair loss, and mouth sores.
Mechanism in Autoimmune Conditions
When used for autoimmune diseases like rheumatoid arthritis, methotrexate operates through a different pathway that focuses on reducing inflammation. At the lower doses prescribed for these conditions, its primary benefit comes from its ability to modulate the immune system rather than halt cell division. This action centers on the accumulation of a molecule called adenosine in the tissues surrounding inflamed joints.
Methotrexate indirectly leads to an increase in extracellular adenosine, a compound with potent anti-inflammatory properties. It achieves this by causing an internal buildup of a precursor molecule, which in turn inhibits enzymes that would normally break down adenosine. The resulting higher concentration of adenosine outside the cells acts as a signal, binding to receptors on active immune cells and instructing them to decrease their inflammatory activities.
This adenosine-mediated pathway calms the aberrant immune response that characterizes autoimmune disorders. It leads to reduced production of pro-inflammatory signals and suppresses the activity of T-cells and B-cells, the immune cells driving the attack on the body’s own tissues. This immunomodulatory effect is the principal reason for the drug’s success in managing chronic inflammatory conditions.
The Role of Folic Acid Supplementation
Physicians often prescribe folic acid or its active form, folinic acid, to be taken alongside methotrexate, particularly for autoimmune conditions. This practice is not meant to counteract the drug’s primary therapeutic action but rather to lessen its side effects. The supplemental folate helps protect the body’s healthy cells from the full impact of DHFR inhibition.
The goal of supplementation is to provide just enough folate for healthy, rapidly dividing cells—like those in the bone marrow and digestive tract—to carry out their necessary functions. This measured dose helps reduce the incidence of side effects such as nausea and mouth ulcers. It creates a rescue pathway for non-immune cells without compromising the drug’s anti-inflammatory benefits.
Taking folic acid as prescribed does not interfere with the adenosine-mediated anti-inflammatory mechanism that is effective in treating autoimmune diseases. It allows patients to tolerate the medication better over the long term while still benefiting from its immunomodulatory effects. This balanced approach makes treatment safer and more sustainable for individuals managing chronic conditions.