Pharmacogenetics as a molecular basis for individualized drug therapy: Thethiopurine S-methyltransferase paradigm

Genetic polymorphism of drug metabolizing enzymes can be the major determin ant of inter-individual differences in drug disposition and effects. In thi s mini-review, the evolution of pharmacogenetic studies, from the recogniti on of phenotypic polymorphisms to the discovery of genetic mutations respon sible for these inherited traits, is illustrated by the genetic polymorphis m of thiopurine S-methyltransferase (TPMT). TPMT, which exhibits autosomal co-dominant polymorphism, plays an important role in metabolism of the anti leukemic and immunosuppressive medications, mercaptopurine, thioguanine, an d azathioprine. The genetic polymorphism of TPMT activity in humans was fir st reported in 1980, and in the last five years the genetic basis for this polymorphism has been elucidated. Isolation and cloning of mutant alleles f rom humans with TPMT deficiency has identified the major mutant alleles, es tablished the basis for loss of TPMT activity and permitted development of PCR-based genotyping assays to make a molecular diagnosis of TPMT-deficienc y and heterozygosity. These studies illustrate the potential clinical benef its of elucidating the molecular basis of inherited differences in drug met abolism and disposition, and future automation of molecular diagnostics wil l make it feasible to more precisely select the optimal drug and dosage for individual patients.