American Board of Surgery Qualifying Exam (ABS QE) Practice Test

Which mechanism of action does Methotrexate primarily utilize?

1. Inhibits dihydrofolate reductase

2. Inhibits thymidylate synthase

3. Inhibits topoisomerase II

4. Inhibits RNA polymerase

The correct answer is: Inhibits dihydrofolate reductase

Methotrexate primarily inhibits dihydrofolate reductase, an enzyme that plays a crucial role in the folate metabolism pathway. This enzyme is responsible for the reduction of dihydrofolate to tetrahydrofolate, which is essential for the synthesis of nucleotides and, consequently, DNA. By inhibiting dihydrofolate reductase, Methotrexate effectively reduces the availability of tetrahydrofolate, resulting in decreased production of the building blocks necessary for DNA synthesis and repair. This mechanism is particularly important in the treatment of rapidly proliferating cells, such as those seen in certain cancers and during inflammatory conditions, where the demand for DNA synthesis is heightened. The inhibition of this enzyme is what gives Methotrexate its cytotoxic and anti-inflammatory properties, making it a commonly used medication in oncology and rheumatology. While thymidylate synthase, topoisomerase II, and RNA polymerase are enzymes involved in various aspects of nucleic acid metabolism and replication, Methotrexate does not primarily target these pathways in its mechanism of action.