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Thiopurine Methyltransferase Activity

Azathioprine (Imuran) and 6-mercaptopurine (Purinethol, 6-MP) are thiopurine drugs that are used to treat neoplasms such as acute lymphoblastic leukemia and a variety of rheumatologic, dermatologic, and neurologic diseases which are believed to have an immune etiology.Both drugs are metabolized to purine nucleotides, which are subsequently incorporated into DNA. This step is necessary for their antimetabolite activity and therapeutic efficacy.

The enzyme, thiopurine methyltransferase (TPMT), provides a competitive pathway for inactivation of these drugs by thiol methylation. A balance must be established between these 2 competing metabolic pathways such that sufficient drug is converted to 6-thiguanine to act as an antimetabolite, but the level does not become so high as to cause lethal bone marrow suppression.

Thiopurine Methyltransferase Activity

Distinct inheritable differences in levels of red blood cell TPMT have been detected among patients.Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelosupression if conventional doses are given.

Approximately 10% of the population has intermediate TPMT activity, while 0.3% has low or absent TPMT activity. Between 30 and 60% of individuals with intermediate TPMT activity cannot tolerate a full thiopurine dose. They should be prescribed a 30 to 70% reduction in thiopurine dose. Homozygous individuals with low TPMT activity require approximately 90% reduction in thiopurine dose or be treated with an alternative medication.

Ideally, TPMT activity should be determined before prescribing immediate full doses of a thiopurine. If therapy cannot be delayed, immediate full doses can be administered and then the dose can be adjusted based on TPMT results. This strategy is permissable because most patients do not reach steady-state concentrations of thioguanine nucleotide metabolites for 2 to 6 weeks.

TPMT phenotyping quantitates TPMT enzyme activity in erythrocytes. The activity of TPMT is measured as the nanomoles of 6-methylmercaptopurine (inactive metabolite) produced per 1 mL of packed red blood cells and expressed as U/mL. Reference ranges at ARUP Laboratories are:

TPMT Level Interpretation
24.0-44.0 U/mL RBC Normal TPMT activity
17.0-23.9 U/mL RBC Intermediate activity
0 - 17.0 U/mL RBC Low TPMT activity

Patients with higher than normal TPMT activity may appear to be therapeutic failures because they metabolize thioguanine nucleotides too quickly.

Numerous patients have values which are near the cutoff between normal and the heterozygous state due to both assay variability and biological variation. 

TPMT enzyme activity can be inhibited by many drugs including, but not limited to: naproxen, ibuprofen furosemide, sulfasalazine, mefenamic acid, thiazide diuretics, and benzoic acid inhibitors. TPMT phenotyping should not be performed for at least 90 days after a red blood cell transfusion. If testing cannot be delayed, TPMT genotyping can be performed.

Four TPMT alleles, TPMT 2, 3A, 3B, and 3C, account for over 90% of inactivating polymorphisms. Therefore, most reference laboratories only test for these genetic variants. Based on the result, a predicted phenotype of normal, intermediate, or low TPMT activity is assigned.

TPMT Genotype Predicted Genotype
1/1 Normal activity
1/2, 1/3A, 1/3B, 1/3C Intermediate activity

2/2, 2/3A, 2/3B, 3A/3C

3A/3A, 3A/3B, 3A/3C

3B/3B, 3B/3C

3C/3C

Low or absent activity

TPMT genotyping should not be performed in patients who have undergone allogeneic bone marrow transplantation, since the result would reflect the donor's genotype, not the patient.

Specimen requirement is one 5 mL green-top (heparin) tube of whole blood. Specimen must be refrigerated and tested within 72 hours of draw.

DiPiero J, Teng K, Hicks JK. Cleveland Clin J Med 2015;82 (7): 409-13.

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