Objective: To systematically investigate the relationships between thiopurine S-methyltransferase (TPMT) polymorphisms and azathioprine-related adverse drug reactions in patients with kidney transplantation.
Methods: Erythrocyte TPMT activity of 150 patients with kidney transplantation and AZA therapy was determined by HPLC. The frequency of four common TPMT mutant alleles, TPMT*2, *3A, *3B, and *3C was determined by allele-specific PCR and PCR-restriction fragment length polymorphism (PCR-RFLP) analysis.
Results: Thirty cases (20%) had stopped azathioprine medication or were on reduced dose due to azathioprine-related side effects. The TPMT activity range of cases who never experienced side effects was 16.63-68.25 U, the mean of the controls was 38.43 +/- 11.59 U. The mean value of 12 cases with hematotoxicity was 23.50 +/- 10.33 U, much lower than the control mean (P < 0.05). No significant difference between the mean value of 18 cases with hepatotoxicity and the control mean (P > 0.05) was seen. No case with TPMT deficiency was found in all patients studied, and TPMT*2, *3A, and *3B were not detected in any of them. TPMT*3C heterozygous alleles were found in 4.7% (seven cases) of these patients, all seven cases had intermediate TPMT activity, and the mean was 16.75 +/- 2.09 U, much lower than other TPMT wild-type patients (P < 0.05). In the seven TPMT*3C patients, four cases experienced side effects (hematotoxicity, n = 2; hepatotoxicity, n = 2).
Conclusions: This study demonstrates that TPMT activity is reduced in patients with TPMT*3C mutation. AZA-induced hematotoxicity is related to the reduced TPMT activity.