UMR CNRS 7200, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, FMTS, Faculté de Pharmacie, Illkirch, France.
Cytometry A. 2013 Apr;83(4):403-8. doi: 10.1002/cyto.a.22263. Epub 2013 Feb 11.
Idiosyncratic drug-induced hepatotoxicity accounts for about 13% of all cases of acute liver failure, therefore cited as the most frequent reason for post-marketing drug withdrawal. Despite this, the underlying mechanisms remain poorly understood due to lack in adequate screening assays and predictive in vitro models. Hepatic transporters play a crucial role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition, including toxicity and loss of efficacy. Inflammation is one condition for demonstrated variable drug response, attributed in part, to changes in function of drug transporters. The present study investigates the implication of two important hepatic transporters (MDR1 and MRP2) in idiosyncratic drug-induced hepatotoxicity in the presence and absence of an inflammatory context. The synergistic effect of idiosyncratic drugs (Trovafloxacin, nimesulide, telithromycin, and nefazodone) and inflammatory stimuli (TNF-α + LPS) on the efflux activity of hepatic transporters was studied using microvolume cytometry. Our results demonstrated on the one hand that both MDR1 and MRP2 are variably implicated in idiosyncratic drug-induced liver injury and on the other hand that the occurrence of an inflammatory reaction during idiosyncratic drug therapy can noticeably modulate this implication. In the absence of an inflammatory stress, none of the four tested drugs modulated the efflux activity of MRP2; nevertheless telithromycin and nefazodone inhibited the efflux activity of MDR1. Upon occurrence of an inflammatory stress, the inhibitory potential of trovafloxacin, nimesulide, and nefazodone on the efflux activity of MRP2 was noticeably revealed, while the telithromycin and nefazodone-induced inhibition of MDR1 was clearly attenuated. Knowledge of underlying mechanisms may significantly contribute to elimination of potential hepatotoxic drugs long before marketing and to prevention of drug-induced hepatotoxicity.
药物性肝损伤的个体差异约占所有急性肝衰竭病例的 13%，因此被认为是上市后药物撤市的最常见原因。尽管如此，由于缺乏充分的筛选检测和预测性体外模型，其潜在机制仍知之甚少。肝转运蛋白在内外源底物和外源性物质的吸收、分布和消除中起着至关重要的作用。转运蛋白功能的缺陷可导致药物处置的改变，包括毒性和疗效丧失。炎症是药物反应个体差异的一个条件，部分归因于药物转运蛋白功能的变化。本研究调查了两种重要的肝转运蛋白（MDR1 和 MRP2）在存在和不存在炎症环境下的药物性肝损伤的个体差异中的作用。使用微量细胞术研究了药物性肝损伤（曲伐沙星、尼美舒利、泰利霉素和奈法唑酮）和炎症刺激（TNF-α+LPS）协同作用对肝转运体外排活性的影响。我们的结果一方面表明，MDR1 和 MRP2 均不同程度地参与了药物性肝损伤，另一方面，在药物性肝损伤治疗过程中发生炎症反应会明显调节这种参与。在没有炎症应激的情况下，四种测试药物均未调节 MRP2 的外排活性；然而，泰利霉素和奈法唑酮抑制了 MDR1 的外排活性。发生炎症应激时，曲伐沙星、尼美舒利和奈法唑酮对 MRP2 外排活性的抑制作用明显显现，而泰利霉素和奈法唑酮诱导的 MDR1 抑制作用明显减弱。了解潜在机制可能会在药物上市前显著有助于消除潜在的肝毒性药物，并预防药物性肝损伤。
