TPMT Polymorphism: When Shield Becomes Weakness

Abstract

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., [Formula: see text], [Formula: see text], [Formula: see text]) 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.

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations

“…Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyzes thiopurines, including 6-mercaptopurine (6-MP) and azathioprine metabolism. The association of TPMT with thiopurines toxicity, especially 6-MP in pediatric leukemia, has been the role model of PGx implication in the clinic 75,76 . None of the TPMT low activity alleles were detected in the current group.…”

Pharmacogenetics and pharmacogenomics: The impact of the single nucleotide polymorphisms in drug response

“…Ovi lekovi se koriste u lečenju leukemija i autoimunskih bolesti. Identifikovano je više od 20 alelskih varijanti TPMT gena, pri čemu TPMT*2, TPMT*3A i TPMT*3C aleli najčešće utiču na smanjenu aktivnost TPMT enzima (30,31). Približno 90% bele populacije ima visoku TPMT enzimsku aktivnost, 10% umerenu aktivnost (heterozigotni nosioci) i 0,3% slabu ili uopšte nema TPMT enzimsku aktivnost.…”

Thiopurine methyltransferase activity in children with acute myeloid leukemia

“…It follows a trimodal pattern of distribution controlled by genetic polymorphisms, with TPMT L (low-activity variant alleles TPMT * 2-* 38) or TPMT H (high-activity wild-type allele TPMT * 1) at a single genetic locus. Overall, 0.3% of the Caucasian population are TPMT-deficient (homozygous TPMT L /TPMT L genotype), 11% exhibit intermediate TPMT activity (heterozygous TPMT L /TPMT H genotype) and 89% exhibit high TPMT activity (TPMT H /TPMT H genotype) (9,11,12). At present, the reason for the unequal distribution of TPMT activity in the intermediate-and high-activity groups remains unknown.…”

“…TPMT activity is associated with sensitivity and toxicity to thiopurines within individuals (11). People who are homozygous for nonfunctional TPMT alleles (TPMT L /TPMT L genotype) develop severe and potentially fatal 6-MP-induced hematologic toxicity (11).…”