Title: Clinical Significance of Thiopurine S-Methyltransferase Gene Polymorphisms
Volume: 5
Issue: 2
Author(s): Shu-Feng Zhou and Balram Chowbay
Affiliation:
Keywords:
Thiopurine methyltransferase, single nucleotide polymorphism, ethnicity, enzyme activity, toxicity
Abstract: Thiopurine methyltransferase (TPMT) is an important enzyme that catalyzes the S-methylation of a series of thiopurine drugs, including 6-mercaptopurine (6-MP), thioguanine and azathiopurine (AZA), to generate inactive methylated metabolites. Thiopurine drugs are widely used to treat malignancies such as acute lymphoblastic leukemia, autoimmune diseases (e.g. inflammatory bowel disease and rheumatoid arthritis), and organ transplant rejection. TPMT activity and TPMT gene exhibit marked polymorphic phenomenon among all ethnic populations studied, though ethnic differences are always observed. To date, a number of TPMT alleles have been identified. The three major alleles of TPMT, namely TPMT *2, *3A and *3C, lead to intermediate and low enzyme activity in 80-95% carriers. Almost all alleles of TPMT result from single nucleotide polymorphisms (SNPs). Patients with very low levels of TPMT activity due to genetic mutation suffer from greatly increased risk for thiopurine-induced toxicity such as myelosuppression when treated with standard doses of thiopurine drugs, while subjects with very high activity may be under-treated. Drug interactions, less frequently observed, may occur due to TMPT induction or inhibition when thiopurine drugs are combined with other agents. It is important to identify the TPMT mutant alleles with functional impact and the clinical relevance to thiopurine therapy. This allows us to avoid severe toxicity and improve therapeutic outcome by tailoring dosage and regimens in individual patients.
