ABSTRACT

Azathioprine (Aza) is a purine antimetabolite immunosuppressant that is widely employed for immunosuppressive therapy in post-transplant recipients or patients with autoimmune diseases. Chronic use of immunosuppressants might produce several side effects, including a high rate of neoplasms in these patients. Considering that genotoxic effects are associated with an increased risk of developing cancer, the aim of this study was to examine the recombinogenic, genotoxic, and cytotoxic effects of Aza using Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster, as well as comet and micronucleus assays in mouse bone marrow cells. Further, the adverse effects of Aza were determined in mouse hepatic and renal tissues using histopathological analysis. Data demonstrated that Aza induced significant increased genotoxicity in D. melanogaster and mouse bone marrow cells at all concentrations tested. Homologous recombination was the predominant genotoxic event noted for the first time to be initiated by Aza in SMART. In histopathological analysis, Aza did not show any marked toxic activity in mouse hepatic and renal tissues. Therefore, the high rate of neoplasms reported in patients with long-term use of Aza may be attributed, at least partially, to the genotoxic action of this drug.

摘要

硫唑嘌呤 (Aza) 是一种嘌呤抗代谢物免疫抑制剂，广泛用于移植后受者或自身免疫性疾病患者的免疫抑制治疗。长期使用免疫抑制剂可能会产生多种副作用，包括这些患者的肿瘤发生率很高。考虑到基因毒性作用与患癌症的风险增加有关，本研究的目的是使用体细胞突变和重组试验 (SMART) 在黑腹果蝇中检查 Aza 的重组、基因毒性和细胞毒性作用，以及小鼠骨髓细胞中的彗星和微核分析。此外，使用组织病理学分析在小鼠肝和肾组织中确定了 Aza 的不良反应。数据表明，在所有测试浓度下，Aza 均在黑腹果蝇和小鼠骨髓细胞中诱导显着增加的遗传毒性。同源重组是 Aza 在 SMART 中首次发现的主要基因毒性事件。在组织病理学分析中，Aza 在小鼠肝肾组织中未显示出任何明显的毒性活性。因此，长期使用 Aza 的患者报告的高肿瘤发生率可能至少部分归因于该药物的基因毒性作用。