Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions

Abstract

The thiopurine S-methyltransferase (TPMT) genetic polymorphism is one of the most 'mature' examples in pharmacogenetics. That is true because of its importance clinically for the individualization of thiopurine drug therapy and also because TPMT has provided novel insights into molecular mechanisms responsible for the functional effects of common genetic polymorphisms. This review will summarize the development of our understanding of the role of inheritance in the regulation of TPMT as well as the clinical implications of that genetic regulation. It will also summarize recent studies in which TPMT pharmacogenetics has enhanced our understanding of molecular mechanisms by which common polymorphisms influence or alter function. TPMT pharmacogenetics highlights the potential clinical importance of the translation of pharmacogenetics from bench to bedside, the potential for basic pharmacogenetic research to provide insight into mechanisms by which genetic polymorphisms can alter function, and the challenges associated with the achievement of both of those goals.

Human 3β-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics

“…3). The most common mechanism by which nonsynonymous cSNPs affect function is an alteration in protein level [39], and decreased protein quantity under these circumstances is most often due to accelerated degradation of the variant allozyme [25,39]. Therefore, we tested the possibility that this HSD3B1 Phe96 variant allozyme might be degraded more rapidly than the WT.…”

“…Transcription and translation of HSD3B1 and HSD3B2 allozymes were performed with the TNT® coupled rabbit reticulocyte lysate (RRL) System (Promega), as described by Wang et al [23][24][25]. Specifically, 1 µg of expression construct DNA, together with 2 µL T7 buffer, 1 µL T7 polymerase, 1 µL of a mixture of amino acids that lacked methionine, 1 µL RNasin (Promega) and 2 µL of 35 S-methionine (1000 Ci/mM, 10 mCi/mL, 0.4 µM final concentration) (Amersham Pharmacia Biotech) were added to 25µL RRL that had been "treated" to inhibit protein degradation.…”

Metabolism and Toxicity of Drugs. Two Decades of Progress in Industrial Drug Metabolism

“…Advances in the field of genetics have had a major impact on drug metabolism and have provided the experimental tools with which to probe the genetic basis for inter-subject variability in human drug pharmacokinetics, metabolism, and toxicity (19)(20)(21)(22). A growing understanding of pharmacogenomics has led to the implementation of clinical genotyping in connection with the use of certain narrow therapeutic index drugs such as the thiopurine derivatives azathioprine and 6-mercaptopurine for acute lymphoblastic lymphoma (23,24) and the colorectal cancer agent irinotecan (25). In the case of the former agents, a genetic polymorphism in thiopurine S-methyltransferase (TPMT*3) is now known to be responsible for profound inter-subject variability in drug exposure and associated safety margins that necessitates dosage adjustments, while SN-38, an active metabolite of irinotecan, is cleared primarily via glucuronidation catalyzed by UGT1A1, of which the *28 allelic variant results in the reduced expression of the enzyme and influences the ratio of SN-38 to its inactive glucuronide conjugate.…”

Dermatology in the Postgenomic Era

“…Studies show that the TPMT activity levels inversely correlate with toxic metabolite levels and bone marrow suppression. 15,16 Pretreatment knowledge of the patient's TPMT genotype guides clinician dosing, with the 10% of patients with low or intermediate TPMT activity receiving consideration for dosage adjustment. Similar tests are currently being used to test for P450 enzymes such as CYP2C9 with warfarin or CYP2D6 for tamoxifen because these enzymes can reduce the time to achieve proper therapeutic levels and reduce toxic effects.…”