Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and azathioprine. Human erythrocyte (RBC) TPMT activity is controlled by a common genetic polymorphism. On a genetic basis approximately one in every 300 subjects lacks TPMT activity, and 11% of subjects have intermediate activities. 6-Thioguanine nucleotides (6-TGN) are major metabolites of 6-MP and azathioprine in humans. RBC 6-TGN concentrations are correlated directly with risk for the development of leukopenia in patients treated with thiopurine drugs. Our studies were performed to determine whether there was a relationship between genetically controlled levels of RBC TPMT activity and RBC concentrations of 6-TGN. We found a significant negative correlation between RBC TPMT activity and 6-TGN concentrations in blood samples from 40 children with acute lymphoblastic leukemia receiving long-term therapy with 6-MP (rs = − 0.474; P < 0.005). In addition, RBC TPMT activities were significantly higher in blood samples from these patients than in blood samples from adult control subjects (P < 0.0001) or children with acute lymphoblastic leukemia who were in remission but were not receiving drug therapy (P < 0.0001). Finally, three adult patients were studied who developed very high RBC 6-TGN concentrations and thiopurine-induced leukopenia. Two of the three patients had no detectable RBC TPMT activity—presumably on a genetic basis. These results indicate that low TPMT activity may be a risk factor for the occurrence of elevated 6-TGN concentrations and for the development of severe leukopenia in patients treated with thiopurine drugs. Measurement of RBC TPMT activity might make it possible to predict this risk factor for the development of thiopurine drug toxicity. Clinical Pharmacology and Therapeutics (1987) 41, 18–25; doi:10.1038/clpt.1987.4

Thiopurine pharmacogenetics in leukemia: Correlation of erythrocyte thiopurine methyltransferase activity and 6-thioguanine nucleotide concentrations