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 sulfhydryl compounds, including Azathioprine (AZA). It has been reported that the level of AZA toxicity is dependent on the TPMT genotypes in Caucasian individuals; 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 effects were investigated in each subject, and were compared between the patients with or without TPMT mutation. RESULTS: The TPMT allelotype was TPMT*1/TPMT*1 in 33 (91.7%) and TPMT*1/TPMT*3C in 3 (8.3%) individuals. All 3 patients (100%) with the mutant TPMT allele (TPMT*3C) discontinued AZA treatment due to leucopenia while only 4 patients (12%) without mutant TPMT alleles showed leucopenia (p=0.0049, Fisher's exact test). However, leucopenia developed relatively late in patients with mutant TPMT. CONCLUSION: The TPMT mutant allele, TPMT*3C, also exists in Japanese individuals, and the bone marrow toxicity of AZA is likely stronger in patients with this mutant allele.