The TPMT (thiopurine S-methyltransferase) gene is essential for metabolizing thiopurine drugs, which include 6-mercaptopurine (6-MP), 6-thioguanine (6-TG), and azathioprine. These drugs are primarily used to suppress the immune system in treating autoimmune disorders like Crohn’s disease and rheumatoid arthritis, certain cancers, and to prevent organ rejection for transplant patients. The TPMT enzyme facilitates the S-methylation of thiopurines, converting them into inactive, non-toxic forms to prevent excessive immune suppression and toxic buildup (Urbančič et al., 2025).

The TPMT enzyme interacts with S-adenosyl-L-methionine as a methyl donor, allowing for proper drug metabolism. In individuals with reduced TPMT activity, thiopurine drugs remain active longer than intended, leading to myelosuppression, which suppresses bone marrow function. This can result in anemia, abnormal bleeding, immune deficiencies, and an increased risk of infections due to a lack of white and red blood cells. Without proper TPMT activity, patients may suffer from severe, potentially life-threatening side effects from thiopurine treatments.

From a clinical perspective, variations in the TPMT gene have a significant impact on drug safety and effectiveness. Every person inherits two copies of the TPMT gene, which can be high-activity, low-activity, or a combination of both. Those who inherit two low-activity copies are at the highest risk of experiencing toxic side effects when taking thiopurine drugs, requiring substantially lower doses or alternative treatments. Individuals with one low-activity and one high-activity copy have moderate risk, meaning they may still require dosage adjustments. People with two high-activity copies metabolize thiopurines normally and do not require special precautions regarding drug dosage.

Because of these genetic differences, genetic screening for TPMT activity  has become standard practice in individualized medicine. Identifying TPMT variations allows physicians to tailor drug dosages to the patient’s specific genetic makeup, reducing the risk of severe side effects while ensuring treatment remains effective. TPMT testing is particularly important for patients with autoimmune diseases and cancer, as improper metabolism of thiopurines can lead to fatal complications.

Researchers have also shown that certain TPMT variants are more prevalent in different populations. The TPMT3A allele is the most common low-activity variant among Caucasians, while TPMT3C is more frequent in Asians, Africans, and African Americans. These findings underscore the importance of population-specific genetic testing to optimize thiopurine treatments.

The TPMT gene is important for drug metabolism in precision medicine. Its role in thiopurine drug inactivation ensures that immunosuppressive treatments are effective and safe. Genetic testing for TPMT variations is a key tool in personalized medicine, allowing for better treatment planning and minimizing the risk of serious drug reactions. As the field of pharmacogenomics advances, TPMT screening will likely become a standard pre-treatment evaluation to ensure patient safety and improve health outcomes. (Urbančič, et al., 2025)

References

Urbančič, D., Jukič, M., Šmid, A., Gobec, S., Jazbec, J., & Mlinarič-Raščan, I. (2025, 03). Thiopurine S-methyltransferase – An important intersection of drug-drug interactions in thiopurine treatment. Retrieved from Biomedicine & Pharmacotherapy; 184: http://sciencedirect.com/science/article/pii/S0753332225000873