Azathioprine/6-mercaptopurine toxicity: The role of the TPMT gene

Abstract

The thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are widely used in medicine, including inflammatory bowel diseases (IBD). Thiopurine drugs undergo S-methylation catalysed by thiopurine methyltransferase (TPMT) to methylmercaptopurine or oxidation to thiouric acid via xanthine oxidase (XO). Altered TPMT activity predominantly results from single nucleotide polymorphisms (SNPs) in the TPMT gene, which is located on chromosome 6p22.3.In the general population TPMT enzyme activity is normal in 89%, intermediate in approximately 11% and absent in approximately 0.3% of cases. The prevalence of the most frequent single nucleotide polymorphisms (SNPs) in the TPMT gene has been reported to vary worldwide. The mechanisms of AZA/6-MP action are currently unknown. Pharmacogenetics of AZA/6-MP represents an interesting field of research with direct implications in clinical practice. AZA/6- MP metabolization steps, the impact of TPMT gene SNPs on toxicity prediction as well as the 6p loci analysis represents a challenging field of research in IBD and other diseases. When possible, TPMT genotyping prior to the initiation of AZA/6-
MP should be considered to decrease the risk of severe adverse event as well as to identify patients who might benefit from higher doses. Clinicians should be aware that TPMT SNPs do not explain all leucopenic events and that TPMT measurements cannot replace the need for continued monitoring of leucocyte counts in AZA/6-MP treated patients.