Thiopurine methyltransferase genotype and the toxicity of azathioprine in Japanese

Objective Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that preferentially catalyzes the S-methylation of aromatic and heterocyclic sul fhydryl compounds, including Azathioprine (AZA), It has been reported that the level of AZA toxicity is dependent on the TPMT genotypes in Caucasian i ndividuals; we thus investigated this relationship in Japanese. Methods The TPMT genotype was determined using peripheral blood cell DNA obtained from 36 Japanese patients with rheumatic diseases who were treated with AZA, by polymerase chain reaction (PCR) technique. Duration of AZA administration, white blood cell counts before and after AZA administration, and side effe cts were investigated in each subject, and were compared between the patien ts with or without TPMT mutation. Results The TPMT allelotype was TPMT*1/TP MT*1 in 33 (91.7%) and TPMT*1/TPMT*3C in 3 (8.3%) individuals, All 3 patien ts (100%) with the mutant TPMT allele (TPMT*3C) discontinued AZA treatment due to leucopenia while only 4 patients (12%) without mutant TPMT alleles s howed leucopenia (p = 0.0049, Fisher's exact test), However, leucopenia dev eloped relatively late in patients with mutant TPMT. Conclusion The TPMT mu tant allele, TPMT*3C, also exists in Japanese individuals, and the bone mar row toxicity of AZA is likely stronger in patients with this mutant allele.