Genetic polymorphism of thiopurine methyltransferase and thiopurine therapy: from molecular genetics to clinical medicine

Published on January 6, 2009 Updated on November 24, 2021   55 min

Other Talks in the Category: Diseases, Disorders & Treatments

0:04
This lecture focuses on the genetic polymorphism of human thiopurine methyltransferase, and the influence these genetic polymorphisms have on thiopurine therapy, and the lecture will span from molecular genetics to the clinical application of these diagnostics in prescribing and individualizing therapy with thiopurines. Thiopurines include azathioprine, which is a prodrug for mercaptopurine, as well as mercaptopurine, a widely used antileukemic agent, and 6-thioguanine, which is also affected by this polymorphism, although perhaps less dramatically. Each of these medications is inactivated through methylation by this polymorphic thiopurine methyltransferase enzyme, and it's been shown that individuals who inherit low activity of thiopurine methyltransferase have an increased risk of toxicity if treated with the conventional doses of mercaptopurine,and azothioprine and to some extent thioguanine.
1:17
This slide depicts the metabolism of mercaptopurine, abbreviated MP in this slide, which indicates that this medications either activate it to thioguanine nucleotides, abbreviated TGN, by a multi enzymatic process, the first step of which is catalyzed by the enzyme HPRT, or this medication is inactivated either by methylation catalyzed by TPMT, or by the enzyme xanthine oxidase. Both of those enzymes convert mercaptopurine to inactive metabolites that cannot be further activated. In many tissues, the inactivation is controlled by both xanthine oxidase and TPMT, but in hematopoietic tissues, xanthine oxidase activity is very low, if at all, meaning that the inactivation is determined by TPMT, and the activation is determined by HPRT. In that case, you would predict that patients who lack TPMT activity would not inactivate the drug as well, and they would shunt more drug down the activation pathway and accumulate more of the active thioguanine nucleotide metabolites. This slide depicts the same metabolic pathway as on the previous slide,
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Genetic polymorphism of thiopurine methyltransferase and thiopurine therapy: from molecular genetics to clinical medicine

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