Non-TPMT determinants of azathioprine toxicity in inflammatory bowel disease

Abstract

Azathioprine (AZA) follows three metabolic routes: the first is the route to 6-thioguanine (TGN) catalyzed by thiopurine methyltransferase (TPMT) and the other two routes are S-methylation to methylmercaptopurine catalyzed also by TPMT or oxidation to thiouric acid via the enzyme xanthine oxidase. Bone marrow toxicity (BMT) mainly in the form of leucopenia represents a major adverse event during AZA therapy in inflammatory bowel disease (IBD). Single nucleotide polymorphisms (SNPs) in the TPMT gene locus affecting 6-TGN intracellular accumulation play a significant role in the occurrence of side effects including BMT. Conflicting data exist regarding the role of TPMT genotyping or TPMT enzyme activity in predicting AZA toxicity. Although some BMT cases can be explained by TPMT genotyping or enzyme activity in the majority of cases BMT remains unexplained. These limitations in TPMT testing pointed out to other genes involved in AZA metabolization. Many non-TPMT genes were investigated but their clinical importance is controversial. To explore the applicability of TPMT and non-TPMT genotyping for AZA toxicity monitoring, large prospective studies are needed. Until the results of such studies are available, the dose adjustments of AZA should be guided primarily by clinical response and peripheral blood counts.