Thiopurine methyltransferase

Thiopurine methyltransferase (TPMT) is an enzyme that plays a crucial role in the metabolism of thiopurine drugs, which are used in the treatment of various medical conditions, including leukemia, autoimmune diseases, and inflammatory bowel disease. The activity of TPMT varies significantly among individuals due to genetic polymorphisms, which can affect the efficacy and toxicity of thiopurine medications.

Function

TPMT catalyzes the S-methylation of thiopurine drugs, such as azathioprine, 6-mercaptopurine, and thioguanine. This methylation process inactivates the drugs, thereby regulating their therapeutic effects and potential toxicity. The enzyme's activity is crucial for preventing the accumulation of toxic metabolites that can lead to severe adverse effects, such as myelosuppression.

Genetic Polymorphisms

The gene encoding TPMT is highly polymorphic, with several known variants that result in different levels of enzyme activity. Individuals can be classified into three groups based on their TPMT activity:

• High activity (homozygous for the wild-type allele)
• Intermediate activity (heterozygous for one wild-type and one variant allele)
• Low or absent activity (homozygous for variant alleles)

Patients with low or absent TPMT activity are at a higher risk of developing severe toxicity when treated with standard doses of thiopurine drugs. Therefore, genotyping or phenotyping for TPMT activity is recommended before initiating thiopurine therapy to tailor the dosage appropriately.

Clinical Significance

TPMT testing is an important aspect of personalized medicine in the context of thiopurine therapy. By identifying patients with low TPMT activity, healthcare providers can adjust drug dosages to minimize the risk of adverse effects while maintaining therapeutic efficacy. This approach helps in optimizing treatment outcomes and improving patient safety.

Related Enzymes and Pathways

TPMT is part of the broader family of methyltransferases, which are involved in various biological processes, including DNA methylation and protein methylation. The enzyme's activity is also linked to the purine metabolism pathway, which is essential for the synthesis and degradation of purine nucleotides.

See Also

• Azathioprine
• 6-mercaptopurine
• Thioguanine
• Pharmacogenomics
• Myelosuppression
• Personalized medicine