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Pharmacogenetics as a Molecular Basis for Individualized Drug Therapy: The Thiopurine S-methyltransferase Paradigm

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Abstract

Genetic polymorphism of drug metabolizing enzymes can be the major determinant of inter-individual differences in drug disposition and effects. In this mini-review, the evolution of pharmacogenetic studies, from the recognition of phenotypic polymorphisms to the discovery of genetic mutations responsible for these inherited traits, is illustrated by the genetic polymorphism of thiopurine S-methyltransferase (TPMT). TPMT, which exhibits autosomal co-dominant polymorphism, plays an important role in metabolism of the antileukemic and immunosuppressive medications, mercaptopurine, thioguanine, and azathioprine. The genetic polymorphism of TPMT activity in humans was first reported in 1980, and in the last five years the genetic basis for this polymorphism has been elucidated. Isolation and cloning of mutant alleles from humans with TPMT deficiency has identified the major mutant alleles, established the basis for loss of TPMT activity and permitted development of PCR-based genotyping assays to make a molecular diagnosis of TPMT-deficiency and heterozygosity. These studies illustrate the potential clinical benefits of elucidating the molecular basis of inherited differences in drug metabolism and disposition, and future automation of molecular diagnostics will make it feasible to more precisely select the optimal drug and dosage for individual patients.

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Authors and Affiliations

  1. St. Jude Children's Research Hospital, 332 N. Lauderdale, St., Memphis, Tennessee, 38101

    Eugene Y. Krynetski

  2. St. Jude Children's Research Hospital, 332 N. Lauderdale, St., Memphis, Tennessee, 38101; and

    William E. Evans

  3. College of Pharmacy, University of Tennessee, Memphis

    Eugene Y. Krynetski & William E. Evans

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  1. Eugene Y. Krynetski
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Supported in part by the following NIH grants: R37 CA36401, R01 CA78224, and Cancer Center CORE grant CA21765, by a Center of Excellence grant from the State of Tennessee, and by American Lebanese Syrian Associated Charities.

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Krynetski, E.Y., Evans, W.E. Pharmacogenetics as a Molecular Basis for Individualized Drug Therapy: The Thiopurine S-methyltransferase Paradigm. Pharm Res 16, 342–349 (1999). https://doi.org/10.1023/A:1011909315614

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