Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy?

Ann Clin Biochem 2004;41:294-302
doi:10.1258/0004563041201455
© 2004 Royal Society of Medicine

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Review Article


Jeremy Sanderson,
Azhar Ansari,
Tony Marinaki and
John Duley


Departments of Purine Research and Gastroenterology, Guy’s & St Thomas’ Hospitals, London, SE1 7EH, UK;
Departments of Purine Research and Gastroenterology, Guy’s & St Thomas’ Hospitals, London, SE1 7EH, UK;
Departments of Purine Research and Gastroenterology, Guy’s & St Thomas’ Hospitals, London, SE1 7EH, UK;
Departments of Purine Research and Gastroenterology, Guy’s & St Thomas’ Hospitals, London, SE1 7EH, UK

Thiopurines [azathioprine (AZA), 6-mercaptopurine (6-MP) andthioguanine (6-TG)] have a well-established role as immunosuppressiveagents in a variety of chronic inflammatory conditions, haematologicalneoplasia and in transplant rejection. Despite good overallclinical response rates, particularly when used as steroid sparingagents, adverse effects are a limiting problem leading to withdrawalin up to a quarter of patients. Severe myelosuppression is themost serious toxicity occurring early or occasionally laterduring treatment.

An understanding of the competing pathways involved in the metabolismof thiopurines has important implications for predicting someof the more severe toxicity seen with these drugs. Thiopurinemethyl transferase (TPMT) is an enzyme catalysing the methylationof 6-MP, competing with xanthine oxidase (XO) and hypoxanthineguanine phosphoribosyl transferase (HGPRT) to determine theamount of 6-MP metabolised to cytotoxic thioguanine nucleotides.Allelic polymorphisms in the TPMT gene predict the activityof the enzyme such that 1 in 10 of the population are heterozygousand have approximately 50% of normal activity, whilst 1 in 300are completely deficient. As a result, these individuals areat high risk of severe myelosuppression. Conversely, individualswith very high levels of TPMT activity are hyper-methylatorsin whom clinical response is less likely. Prior knowledge ofTPMT status avoids exposure of individuals with zero TPMT topotentially fatal treatment with AZA or 6-MP and provides oneof the best examples of predictive pharmacogenetics in therapeutics.This article reviews literature on the role of TPMT measurementprior to treatment with thiopurines and provides some guidanceto the use of TPMT as a guide to tailoring thiopurine therapy.


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