LACDR, Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Toxicol In Vitro. 2012 Mar;26(2):197-205. doi: 10.1016/j.tiv.2011.11.013. Epub 2011 Nov 26.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation. However, this group of drugs is associated with serious adverse drug reactions. Previously, we studied the mechanisms underlying toxicity of the NSAID diclofenac using Saccharomycescerevisiae as model system. We identified the involvement of several mitochondrial proteins, a transporter and cytochrome P450 activity in diclofenac toxicity. In this study, we investigated if these processes are also involved in the toxicity of other NSAIDs. We divided the NSAIDs into three classes based on their toxicity mechanisms. Class I consists of diclofenac, indomethacin and ketoprofen. Mitochondrial respiration and reactive oxygen species (ROS) play a major role in the toxicity of this class. Metabolism by cytochrome P450s further increases their toxicity, while ABC-transporters decrease the toxicity. Mitochondria and oxidative metabolism also contribute to toxicity of class II drugs ibuprofen and naproxen, but another cellular target dominates their toxicity. Interestingly, ibuprofen was the only NSAID that was unable to induce upregulation of the multidrug resistance response. The class III NSAIDs sulindac, ketorolac and zomepirac were relatively non-toxic in yeast. In conclusion, we demonstrate the use of yeast to investigate the mechanisms underlying the toxicity of structurally related drugs.
非甾体抗炎药（NSAIDs）被广泛用于治疗疼痛和炎症。然而，这组药物与严重的药物不良反应有关。此前，我们使用酿酒酵母作为模型系统研究了 NSAID 双氯芬酸毒性的机制。我们发现几种线粒体蛋白、一种转运蛋白和细胞色素 P450 活性参与了双氯芬酸的毒性。在这项研究中，我们研究了这些过程是否也参与了其他 NSAIDs 的毒性。我们根据毒性机制将 NSAIDs 分为三类。I 类包括双氯芬酸、吲哚美辛和酮洛芬。线粒体呼吸和活性氧（ROS）在这一类的毒性中起主要作用。细胞色素 P450 代谢进一步增加了它们的毒性，而 ABC 转运蛋白则降低了它们的毒性。线粒体和氧化代谢也有助于 II 类药物布洛芬和萘普生的毒性，但另一个细胞靶点主导了它们的毒性。有趣的是，布洛芬是唯一一种不能诱导多药耐药反应上调的 NSAID。III 类 NSAIDs 舒林酸、酮咯酸和唑美昔布在酵母中相对无毒。总之，我们证明了使用酵母来研究结构相关药物毒性的机制。
