The human body contains numerous specialized proteins called enzymes, each designed to perform a particular task. One such enzyme is thiopurine S-methyltransferase, often referred to as TPMT. Its role involves breaking down certain compounds. This enzyme plays a part in how the body processes various substances, including some medications. Understanding its function helps clarify how certain drugs are handled.
The Role of TPMT in Drug Metabolism
TPMT specializes in metabolizing a specific class of medications known as thiopurines, including azathioprine, 6-mercaptopurine, and tioguanine. Thiopurines work by suppressing the immune system, making them valuable in treating a range of conditions. They are prescribed for inflammatory bowel disease (IBD), acute lymphoblastic leukemia (ALL), and various autoimmune disorders. These medications also help prevent organ rejection in transplant recipients. The TPMT enzyme converts these active thiopurine compounds into inactive forms, reducing their potential for toxicity.
Understanding TPMT Deficiency
TPMT deficiency occurs when the body produces a less active or non-functional version of the TPMT enzyme due to variations in the TPMT gene. When a person with this deficiency takes thiopurine medications, the drugs are not metabolized properly and can accumulate in the body. This buildup leads to higher concentrations of the active, toxic forms of the drug within cells. The primary risk associated with this accumulation is severe bone marrow suppression, also known as myelosuppression. Myelosuppression can result in dangerously low levels of blood cells, including red blood cells, white blood cells, and platelets, leading to complications like anemia, increased susceptibility to infections, and excessive bleeding.
TPMT Testing and Interpreting Results
Doctors often recommend TPMT testing before initiating thiopurine drug therapy to identify individuals at risk of severe side effects. There are two main types of tests used to assess TPMT activity or genetic variations. The phenotype test measures the actual activity level of the TPMT enzyme in a person’s red blood cells. The genotype test identifies specific genetic variations in the TPMT gene that affect enzyme function.
Results fall into one of three categories. Most people (about 90%) have normal or high TPMT enzyme activity, meaning they metabolize thiopurines effectively. Individuals with intermediate activity (roughly 10%) have one working copy and one non-working copy of the gene, resulting in reduced enzyme function. A small percentage of people (about 1 in 300) have low or no TPMT activity because they have two non-working gene copies.
Adjusting Medication Based on TPMT Activity
The results from TPMT testing guide doctors in safely determining the appropriate thiopurine drug dosage. For individuals with normal or high TPMT enzyme activity, a standard dose of the thiopurine medication is prescribed. Their bodies metabolize the drug efficiently, minimizing the risk of harmful accumulation.
Patients with intermediate TPMT activity require a significantly reduced dose, often ranging from 30% to 70% of the standard amount. This adjustment helps prevent drug buildup while still allowing the medication to be effective. For those with low or no TPMT activity, thiopurine drugs are avoided altogether due to the high risk of severe toxicity. In such cases, doctors select alternative medications that do not rely on the TPMT enzyme for metabolism. If thiopurines are used, a drastically reduced dose, perhaps around 10% of the standard, may be considered with very close monitoring of blood counts.