In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone
In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone
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DOI：
10.1093/toxsci/kfn056
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发表时间：
2008-06-01
影响因子：
3.8
通讯作者：
Will, Yvonne
中科院分区：
文献类型：
--
作者：
Dykens, James A.;Jamieson, Joseph D.;Will, Yvonne
线粒体毒性越来越多地涉及药物诱导的器官毒性，包括肝毒性。奈法唑酮因肝毒性于2004年退出美国市场。因此，我们评估了奈法唑酮，另一种三唑吡啶曲唑酮，加上氮杂螺烷二酮丁螺环酮的细胞毒性和对线粒体功能的影响。与其临床处置雅阁，奈法唑酮是三种化合物中毒性最大的，曲唑酮的作用相对较小，而丁螺环酮的毒性最小。奈法唑酮深刻抑制线粒体呼吸在离体大鼠肝线粒体和完整的HepG2细胞，这是伴随着糖酵解的同时加速。使用免疫捕获的氧化磷酸化（OXPHOS）复合物，我们确定了复合物1，并以较少量的复合物IV，作为奈法唑酮毒性的目标。未发现曲唑酮有抑制作用，丁螺环酮对OXPHOS复合物1的抑制作用比奈法唑酮低3.4倍。在表达细胞色素P450亚型3A4的人肝细胞中，暴露24小时后，奈法唑酮和曲唑酮使线粒体膜电位崩溃，并通过谷胱甘肽耗竭检测到氧化应激，导致细胞死亡。我们的研究结果表明，奈法唑酮造成的线粒体损伤是深刻的，并可能导致其肝毒性，特别是在与其他药物共同治疗的患者与线粒体负债。
Mitochondrial toxicity is increasingly implicated in a host of drug-induced organ toxicities, including hepatotoxicity. Nefazodone was withdrawn from the U.S. market in 2004 due to hepatotoxicity. Accordingly, we evaluated nefazodone, another triazolopyridine trazodone, plus the azaspirodecanedione buspirone, for cytotoxicity and effects on mitochondrial function. In accord with its clinical disposition, nefazodone was the most toxic compound of the three, trazodone had relatively modest effects, whereas buspirone showed the least toxicity. Nefazodone profoundly inhibited mitochondrial respiration in isolated rat liver mitochondria and in intact HepG2 cells where this was accompanied by simultaneous acceleration of glycolysis. Using immunocaptured oxidative phosphorylation (OXPHOS) complexes, we identified Complex 1, and to a lesser amount Complex IV, as the targets of nefazodone toxicity. No inhibition was found for trazodone, and buspirone showed 3.4-fold less inhibition of OXPHOS Complex 1 than nefazodone. In human hepatocytes that express cytochrome P450, isoform 3A4, after 24 h exposure, nefazodone and trazodone collapsed mitochondrial membrane potential, and imposed oxidative stress, as detected via glutathione depletion, leading to cell death. Our results suggest that the mitochondrial impairment imposed by nefazodone is profound and likely contributes to its hepatotoxicity, especially in patients cotreated with other drugs with mitochondrial liabilities.