GENETIC-POLYMORPHISM OF THIOPURINE S-METHYLTRANSFERASE - CLINICAL IMPORTANCE AND MOLECULAR MECHANISMS

Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of t hiopurines such as mercaptopurine and thioguanine. TPMT activity exhib its genetic polymorphism, with about 1 in 300 inheriting TPMT-deficien cy as an autosomal recessive trait. If treated with standard dosages o f thiopurines, TPMT-deficient patients accumulate excessive thioguanin e nucleotides (TGN) in hematopoietic tissues, leading to severe hemato poietic toxicity that can be fatal. However, TPMT-deficient patients c an be successfully treated with a 10-15-fold lower dosage of these med ications. The human gene encoding polymorphic TPMT has been cloned and characterized, and two mutant alleles have recently been isolated fro m TPMT-deficient and heterozygous patients (TPMT2, TPMT*3), permittin g development of PCR-based methods to identify TPMT-deficient and hete rozygous patients prior to therapy. TPMT3 is the predominant mutant a llele in American whites, accounting for about 75% of mutations in thi s population. Ongoing studies aim to better define the influence of TP MT activity on thiopurine efficacy, to identify additional mutant alle les and determine their frequency in different ethnic groups, to eluci date the mechanism(s) for loss of function of mutant proteins, to iden tify potential endogenous substrates and to define the molecular mecha nisms of TPMT regulation. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy.