Thiopurine SMethyltransferase

The thiopurine S-methyltransferase (TPMT) gene metabolizes thiopurine medications, such as mercaptopurine, azathioprine, and thioguanine. TPMT activity is polymorphic with 10% of the subjects being heterozygous and about 1/300 with low or deficient activity (42,43). Patients with low or deficient TPMT activity are at high risk for severe hematological toxicity from standard doses of thiopurine medications. Thus, it is important to be able to identify those patients who are at risk for such complications. The molecular basis for altered TPMT activity is well characterized with three distinct alleles accounting for up to 95% of both heterozygous and homozygous mutant patients (43). However, significant ethnic differences have been identified in both the frequency of low TPMT activity and in the mutations that account for them (43). Although extended clinical studies are needed to better understand and quantitate the dosing of these drugs, TPMT genotype-specific dosing guidelines have been proposed for the use of mercapto-purine in leukemia patients (44). Given the severity of thiopurine medication-related tox-icity in TPMT-deficient patients, screening of the entire patient populations for TPMT polymorphism prior to prescribing these drugs has been shown to be cost-effective. By determining thiopurine transferase activity in patients before they receive thiopurines, enzyme efficacy can be determined beforehand and life-threatening complications, which are strongly related to the genetically determined activity of this enzyme, can be avoided. Accordingly, screening for genetic variations in the TPMT gene presents an ideal model for the translation of genomic information to guide patient therapeutics.

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