TPMT (thiopurine S-methyltransferase) is a cytoplasmic phase II metabolic enzyme that catalyzes S-methylation of thiopurine drugs including 6-mercaptopurine, 6-thioguanine, and azathioprine using S-adenosyl-L-methionine as the methyl donor 1. TPMT activity modulates the cytotoxic effects of these prodrugs, with no endogenous substrate yet identified. The enzyme is expressed predominantly in liver and kidney tissue 1. TPMT exhibits monogenic codominant inheritance, with variant alleles associated with reduced enzyme activity and pronounced pharmacologic effects 2. Genetic polymorphisms in TPMT are the principal determinant of TPMT phenotype, with chromosome 6 variants showing strongest associations with activity levels 3. Loss-of-function TPMT alleles predispose patients to myelosuppression and bone-marrow depression during thiopurine therapy 4. Clinical implementation of TPMT genotyping is essential before thiopurine initiation to enable personalized dosing 24. Ethnic variation in TPMT polymorphism frequencies is significant, with important implications for thiopurine-treated populations including those with acute lymphoblastic leukemia and autoimmune diseases 15. Current guidelines recommend 50% dose reductions for intermediate metabolizers and 10% for poor metabolizers of thiopurines 4.