Abstract
Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 (NUDT15) polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the NUDT15 studies, mainly in Asian countries, and their implementation in several countries.
Highlights
Thiopurines, 6-mercaptopurine (6-MP) and azathioprine (AZA) are used as immunosuppressive and cytotoxic agents
Thiopurine S-methyltransferase (TPMT) is an enzyme involved in thiopurine metabolism (Figure 1), and its genetic polymorphisms are known to be risk factors for intolerance to thiopurines [6]
This study identified that the NUDT15 c.415C>T (p.R139C) variant was strongly associated with thiopurine-induced early leukopenia
Summary
Thiopurines, 6-mercaptopurine (6-MP) and azathioprine (AZA) are used as immunosuppressive and cytotoxic agents. Med. 2021, 11, 778 other variants have been uncertain about the functional significance, referring to the Pharmacogene Variation Consortium (PharmVar, www.pharmvar.org). The NUDT15 loss-of-function variants induce the increased levels of thiopurine triphosphate and higher incorporation of thioguanine nucleotides into the DNA and RNA. A result, patients who inherited these levels of thiopurine triphosphate and higherAsincorporation of thioguanine nucleotides variants experienced severe thiopurine-induced cytotoxicities, such as myelosuppression into the DNA and RNA. Is commonly detected in Asians but is rarely severe thiopurine-induced cytotoxicities, such as myelosuppression and alopecia. Inof this review,alleles we aimed and their clinical significance, mainly in Asians, as well as their implementation in several to provide a summary of the associations of NUDT15 alleles and their clinical significance, countries. IBD, inflammatory bowel disease; ALL, acute lymphoblastic leukemia; AZA, azathioprine; 6-MP, 6-mercaptopurine
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