Thiopurine methyltransferase

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an is_associated_with::enzyme that in humans is encoded by the TPMT is_associated_with::gene. A pseudogene for this locus is located on chromosome 18q.

Function
Thiopurine methyltransferase methylates is_associated_with::thiopurine compounds. The methyl donor is is_associated_with::S-adenosyl-L-methionine, which is converted to is_associated_with::S-adenosyl-L-homocysteine. This enzyme metabolizes is_associated_with::thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct.

Clinical significance
Thiopurine drugs such as is_associated_with::6-mercaptopurine are used as chemotherapeutic agents and is_associated_with::immunosuppressive drugs. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals.

Pharmacology
TPMT is best known for its role in the metabolism of the is_associated_with::thiopurine drugs such as is_associated_with::azathioprine, is_associated_with::6-mercaptopurine and is_associated_with::6-thioguanine. TPMT catalyzes the S-methylation of thiopurine drugs. Defects in the TPMT gene leads to decreased methylation and decreased inactivation of is_associated_with::6MP leading to enhanced bone marrow toxicity which may cause is_associated_with::myelosuppression, anemia, bleeding tendency, is_associated_with::leukopenia & infection.

Diagnostic use
Measurement of TPMT activity is encouraged prior to commencing the treatment of patients with is_associated_with::thiopurine drugs such as is_associated_with::azathioprine, is_associated_with::6-mercaptopurine and is_associated_with::6-thioguanine. Patients with low activity (10% prevalence) or especially absent activity (prevalence 0.3%) are at a heightened risk of drug-induced bone marrow toxicity due to accumulation of the unmetabolised drug. Reuther et al. found that about 5% of all thiopurine therapies will fail due to toxicity. This intolerant group could be anticipated by routine measurement of TPMT activity. There appears to be a great deal of variation in TPMT mutation, with ethnic differences in mutation types accounting for variable responses to is_associated_with::6MP.

Genetic variants of TPMT have also been associated with is_associated_with::cisplatin-induced is_associated_with::ototoxicity in children. TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.