TPMT Polymorphism: When Shield Becomes Weakness

Thiopurine methyltransferase (TPMT) is a cytoplasmic transmethylase present in both prokaryotes and eukaryotes. In humans, it shows its presence in almost all of the tissues, predominantly in liver and kidney. TPMT is one of the important metabolic enzymes of phase II metabolic pathway and catalyzes methylation of thiopurine drugs such as azathioprine, 6-thioguanine and 6-mercaptopurine, which are used to treat patients with neoplasia and autoimmune disease as well as transplant recipients. In this sense, TPMT acts as shield against toxic effect of these drugs. Pharmacogenomic studies revealed that genetic polymorphism in TPMT is responsible for variable and, in some cases, adverse drug reaction. Those human groups who carry variants of TPMT (i.e., , , ) are at high risk, because they are unable to metabolize thiopurine drugs thus becoming a weakness of patients against these drugs. Keeping in the mind the importance of TPMT, this review discusses the existence and distribution of various TPMT variants throughout different ethnic groups and risk of adverse drug reactions to them, and how they can avoid this risk of side effects. The review also highlighted factors responsible for variable reactions of TPMT, how this TPMT polymorphism can be considered in drug designing process to avoid toxic effects, designing precautions against them and more importantly designing personalized medicine.