Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1/3, 612 42 Brno, Czech Republic.
Dig Dis Sci. 2012 Sep;57(9):2394-401. doi: 10.1007/s10620-012-2163-y. Epub 2012 Apr 26.
Approximately 10-28 % of patients experience adverse drug reactions related to treatment with thiopurines. The most serious reaction is myelosuppression, typically manifested as leucopenia, which occurs in approximately 2-5 % of patients. Other adverse drug reactions that often accompany thiopurine therapy are pancreatitis, hepatotoxicity, allergic reactions, digestive intolerance, arthralgia, febrile conditions, and rash.
The objective of this study was to assess the relationship between variant alleles of thiopurine S-methyltransferase (SNPs 238G > C, 460G > A and 719A > G), inosine triphosphate diphosphatase (SNPs 94C > A and IVS2 + 21A > C), and xanthine dehydrogenase (837C > T) and the occurrence of adverse drug reactions to azathioprine therapy.
Genotype was determined for 188 Caucasians diagnosed with inflammatory bowel disease treated with a standard dose of azathioprine (1.4-2.0 mg/kg/day). Allelic variants were determined by PCR-REA and real-time PCR methods. Results were statistically evaluated by use of Fisher's test and by odds ratio calculation.
Variant genotype thiopurine S-methyltransferase predisposes to development of leucopenia (P = 0.003, OR = 5, CI 95 %, 1.8058-13.8444). Although not statistically significant, we observed a trend that suggested correlation between the occurrence of digestive intolerance and the variant genotype inosine triphosphate diphosphatase (P = 0.1102; OR 15.63, CI 95 %, 1.162-210.1094), and between the occurrence of pancreatitis and the variant allele xanthine dehydrogenase 837T (P = 0.1124; OR 12,1, CI 95 %, 1.15-126.37).
The variant genotype thiopurine S-methyltransferase has been associated with the occurrence of leucopenia. The involvement of polymorphisms in inosine triphosphate diphosphatase and xanthine dehydrogenase genes in the development of digestive intolerance and pancreatitis will require further verification.
约 10-28%的患者在使用硫嘌呤类药物治疗时会出现药物不良反应。最严重的反应是骨髓抑制，通常表现为白细胞减少，约发生在 2-5%的患者中。硫嘌呤类药物治疗常伴随的其他不良反应包括胰腺炎、肝毒性、过敏反应、消化不耐受、关节痛、发热和皮疹。
本研究旨在评估硫嘌呤 S-甲基转移酶（SNP 238G>C、460G>A 和 719A>G）、肌苷三磷酸二磷酸酶（SNP 94C>A 和 IVS2+21A>C）和黄嘌呤脱氢酶（837C>T）的变异等位基因与巯基嘌呤治疗药物不良反应的关系。
对 188 名诊断为炎症性肠病的高加索白人患者进行了研究，这些患者接受了标准剂量的巯基嘌呤（1.4-2.0mg/kg/天）治疗。通过 PCR-REA 和实时 PCR 方法确定等位基因变异。采用 Fisher 检验和比值比计算对结果进行统计学评估。
变异型硫嘌呤 S-甲基转移酶基因易导致白细胞减少（P=0.003，OR=5，95%CI，1.8058-13.8444）。虽然没有统计学意义，但我们观察到一种趋势，表明肌苷三磷酸二磷酸酶的变异基因型与消化不耐受的发生之间存在相关性（P=0.1102；OR 15.63，95%CI，1.162-210.1094），黄嘌呤脱氢酶 837T 等位基因与胰腺炎的发生之间也存在相关性（P=0.1124；OR 12.1，95%CI，1.15-126.37）。
变异型硫嘌呤 S-甲基转移酶基因与白细胞减少的发生有关。肌苷三磷酸二磷酸酶和黄嘌呤脱氢酶基因多态性在消化不耐受和胰腺炎的发生中的作用需要进一步验证。
