Thiopurine methyltransferase (TPMT) is an enzyme naturally present in the body. It plays a role in metabolic processes, helping to break down and modify compounds. TPMT facilitates specific chemical reactions and its function is consistent across various tissues.
The Role of TPMT in Drug Metabolism
TPMT’s function extends to processing a specific class of medications known as thiopurines. These drugs include azathioprine, 6-mercaptopurine, and 6-thioguanine, widely prescribed for their ability to suppress the immune system. Thiopurines manage conditions like Crohn’s disease, ulcerative colitis, certain leukemias, and autoimmune disorders such as rheumatoid arthritis. They also prevent organ rejection.
The enzyme TPMT helps deactivate these thiopurine drugs by converting them into inactive compounds. This metabolic step prevents active drug components from accumulating in the body. Without sufficient TPMT activity, drugs can build up to toxic levels, potentially causing severe side effects, most notably bone marrow suppression. Myelosuppression can lead to dangerously low levels of blood cells, affecting the body’s ability to fight infection or clot blood.
Genetic Variations in TPMT Activity
Individual differences in TPMT function stem from variations in the TPMT gene, which provides instructions for making the enzyme. Each person inherits two copies of this gene, one from each parent. Variations within these gene copies can result in an enzyme that functions less efficiently, or not at all.
These genetic differences lead to a range of TPMT activity levels:
Most people (89% to 94%) have two normal gene copies, resulting in high or normal enzyme activity.
About 6% to 11% carry one normal and one variant copy, leading to intermediate activity.
A smaller group (around 0.3%) inherits two variant copies, resulting in very low or deficient activity.
TPMT Testing and Result Interpretation
Determining a person’s TPMT status involves specific laboratory tests, typically performed before starting thiopurine therapy. There are two primary types of tests: phenotype testing and genotype testing.
Phenotype testing measures the actual amount of TPMT enzyme activity in a person’s red blood cells. This test indicates how effectively the enzyme is working at the time of the blood draw.
Genotype testing analyzes a person’s DNA to identify specific variations in the TPMT gene. This test reveals the genetic makeup influencing TPMT activity, unaffected by temporary factors like blood transfusions.
Both tests aim to predict a patient’s risk of developing severe side effects from thiopurine drugs. The interpretation of test results categorizes individuals into different metabolizer statuses. A result indicating normal TPMT activity suggests a low risk of toxicity with standard thiopurine doses. Patients with intermediate TPMT activity are at an increased risk for side effects, as their enzyme processes the drugs more slowly. A result showing low or deficient TPMT activity means the individual is at a high risk of severe, potentially life-threatening toxicity if given standard doses.
Adjusting Treatment Based on TPMT Levels
Understanding a patient’s TPMT status directly influences thiopurine treatment, ensuring both safety and effectiveness. For individuals with normal TPMT enzyme activity, healthcare providers typically prescribe the standard dose of thiopurine medication. This dosage is generally well-tolerated, as their bodies can effectively break down the drug, minimizing the risk of harmful accumulation.
Patients identified with intermediate TPMT activity face a higher likelihood of experiencing side effects with conventional dosing. For these individuals, the initial thiopurine dose is commonly reduced, often by 30% to 70% of the standard amount. This dose adjustment helps prevent excessive drug buildup while still aiming for therapeutic benefits, though close monitoring of blood counts remains necessary.
When a patient has low or deficient TPMT activity, the risk of severe toxicity, particularly bone marrow suppression, is very high. In such cases, a drastic reduction in dosage, possibly by 90% or more, is often recommended, sometimes with the medication given only a few times per week instead of daily. More commonly, an entirely different medication that is not metabolized by TPMT is chosen to avoid life-threatening complications.