TPMT Genotyping

Thiopurine methyltransferase (TPMT) is the primary enzyme responsible for thiopurine drug based metabolism. Thiopurine drugs (azathioprine, 6-mercaptopurine and 6-thioguanine) require conversion to thioguanine nucleotides to exert their therapeutic (cytotoxic) effect; however that conversion can be blocked by methylation or oxidation. The methylation pathway depends on TPMT activity.

 TPMT activity is significantly affected by a common genetic polymorphism found in the TPMT gene. Approximately, 89% of the population have high enzyme activity and are homozygous for the normal allele, 11% inherit intermediate levels of enzyme activity with one normal and one variant allele, while 1 in 300 have no functional activity (two variant alleles, homozygous TPMT) ¹. Thioguanine nucleotides can accumulate in patients who have reduced TPMT activity and who are receiving standard thiopurine doses, which lead to severe and possibly fatal myelosuppression.

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