Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase.
Thiopurine drugs are used to treat patients with neoplasia and autoimmune disease as well as transplant recipients. These agents are metabolized, in part, by S-methylation catalyzed by thiopurine methyltransferase (TPMT). The discovery nearly two decades ago that levels of TPMT activity in human tissues are controlled by a common genetic polymorphism led to one of the best examples of the potential importance of pharmacogenetics for clinical medicine. Specifically, it is now known that patients with inherited very low levels of TPMT activity are at greatly increased risk for thiopurine-induced toxicity such as myelosuppression when treated with standard doses of these drugs, while subjects with very high activity may be undertreated. Furthermore, recent reports indicate that TPMT may be the target for clinically significant drug interactions and that this common genetic polymorphism might be a risk factor for the occurrence of therapy-dependent secondary leukemia. In parallel with these clinical reports, the molecular basis for the TPMT polymorphism has been determined as a result of cloning and characterization of the human TPMT cDNA and gene. Those advances led to the description and characterization of a series of single nucleotide polymorphisms that result in low levels of enzyme activity as well as a polymorphic variable number tandem repeat within the 5'-flanking region of the TPMT gene that may "modulate" level of enzyme activity. As a result of these observations, the TPMT genetic polymorphism represents a model system for the way in which basic pharmacogenetic information is developed and applied to clinical medicine.
Weinshilboum
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Department of Pharmacology, Mayo Medical School/Mayo Graduate School/Mayo Clinic, Rochester, Minnesota 55905, USA. weinshilboum.richard@mayo.edu
D006801:Humans; D008780:Methyltransferases / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011687:Purines / Q000627:therapeutic use*
D011687:Purines; D008780:Methyltransferases; C022745:thiopurine methyltransferase