Ferjani H, Achour A, Bacha H, Abid S
Laboratory of Research on Biologically Compatible Compounds, Faculty of Dentistry, Monastir, Tunisia.
Department of Nephrology, Dialysis and Transplant, University Hospital of Sahloul, Sousse, Tunisia.
Hum Exp Toxicol. 2015 Nov;34(11):1119-32. doi: 10.1177/0960327115569812. Epub 2015 Feb 2.
Gastrointestinal risk factors after organ transplantation are prevalent, due to the chronic use of immunosuppressant. The immunosuppressive drugs such as tacrolimus/mycophenolate mofetil (TAC/MMF) association are the most commonly used therapy. TAC and MMF have been implicated in gastrotoxicity, but their direct effects, alone and combined, on intestinal cells are not completely elucidated. This study investigated the effect of TAC and MMF alone and combined on human colon carcinoma cells. Our results demonstrated that TAC and MMF individually inhibit clearly cells proliferation, enhanced free radicals, lipid peroxidation production, induced DNA lesions and reduced mitochondrial membrane potential. In this study, we also showed that the two molecules TAC and MMF combined at high concentrations amplified the cell damage. Furthermore, the TAC (5 µM) prevented cell death induced by MMF (half maximal inhibitory concentration (IC(50))). Also, MMF (50 µM) induced cytoprotection in HCT116 cells against TAC (IC(50)) toxicity. Our findings provide additional evidence that oxidative damage is the major contribution of TAC and MMF combined toxicities. In fact, MMF and TAC exert a gastroprotective effect by modulating reactive oxygen species production. These data underscore the pleiotropic effect of TAC and MMF on HCT116 cells that play a preventive and critical role on intestinal function.
由于长期使用免疫抑制剂，器官移植后的胃肠道危险因素很普遍。免疫抑制药物如他克莫司/霉酚酸酯（TAC/MMF）联合使用是最常用的治疗方法。TAC和MMF与胃毒性有关，但其单独及联合对肠道细胞的直接作用尚未完全阐明。本研究调查了TAC和MMF单独及联合对人结肠癌细胞的影响。我们的结果表明，TAC和MMF单独使用均能明显抑制细胞增殖，增加自由基、脂质过氧化产物的生成，诱导DNA损伤并降低线粒体膜电位。在本研究中，我们还表明，高浓度的TAC和MMF联合使用会加剧细胞损伤。此外，TAC（5 μM）可预防MMF（半数最大抑制浓度（IC50））诱导的细胞死亡。同样，MMF（50 μM）可诱导HCT116细胞对TAC（IC50）毒性产生细胞保护作用。我们的研究结果提供了额外的证据，表明氧化损伤是TAC和MMF联合毒性的主要原因。事实上，MMF和TAC通过调节活性氧的产生发挥胃保护作用。这些数据强调了TAC和MMF对HCT116细胞的多效性作用，这些作用对肠道功能起着预防和关键作用。
