Clinical Pharmacogenomics of Thiopurine S-methyltransferase

Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP), thioguanine and azathioprine (AZA). These drugs are used to treat conditions such as acutelymphoblastic leukemia, inflammatory bowel disease, rheumatoid arthritis, and organ transplant rejection. This reviewhighlights the polymorphisms of TPMT gene and their clinical impact on the use of thiopurine drugs. To date, there are 18known mutational TPMTalleles. The three main TPMT alleles, namely TPMT *2, *3A and *3C, account for 80 - 95% ofthe intermediate and low enzyme activity. The TPMT gene exhibits significant genetic polymorphisms among all ethnicgroups studied. Patientswho inherited very low levels of TPMT activity are at greatlyincreased risk for thiopurine-induced toxicity such as myelosuppression,when treated with standard doses of these drugs, while subjectswith very highactivity may be undertreated. Moreover, clinical drug interactions may occur due to TMPT induction or inhibition.Identification of the TPMTmutant alleles allows physicians to tailor the dosage of the thiopurine drugs to the genotype ofthe patient or to use alternatives, improving therapeutic outcome