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首页> 外文期刊>The Journal of toxicological sciences >A rapid mitochondrial toxicity assay utilizing rapidly changing cell energy metabolism
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A rapid mitochondrial toxicity assay utilizing rapidly changing cell energy metabolism

机译：利用迅速改变细胞能量代谢的快速线粒体毒性测定

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摘要

Drug-induced liver injury is a major cause of safety-related drug-marketing withdrawals. Several drugs have been reported to disrupt mitochondrial function, resulting in hepatotoxicity. The development of a simple and effective in vitro assay to identify the potential for mitochondrial toxicity is thus desired to minimize the risk of causing hepatotoxicity and subsequent drug withdrawal. An in vitro test method called the "glucose-galactose" assay is often used in drug development but requires prior-culture of cells over several passages for mitochondrial adaptation, thereby restricting use of the assay. Here, we report a rapid version of this method with the same predictability as the original method. We found that replacing the glucose in the medium with galactose resulted in HepG2 cells immediately shifting their energy metabolism from glycolysis to oxidative phosphorylation due to drastic energy starvation; in addition, the intracellular concentration of ATP was reduced by mitotoxicants when glucose in the medium was replaced with galactose. Using our proposed rapid method, mitochondrial dysfunction in HepG2 cells can be evaluated by drug exposure for one hour without a pre-culture step. This rapid assay for mitochondrial toxicity may be more suitable for high-throughput screening than the original method at an early stage of drug development.
机译：药物诱发的肝损伤是与安全相关的药物营销提款的主要原因。据报道，几种药物扰乱了线粒体功能，导致肝毒性。因此，期望鉴定线粒体毒性的潜力的简单且有效的体外测定的发展，以最大限度地减少引起肝毒性和随后的药物戒断的风险。一种称为“葡萄糖 - 半乳糖”测定的体外测试方法通常用于药物发育中，但需要在微粒适应的几个通道上进行细胞的先前培养，从而限制测定的使用。在这里，我们报告了这种方法的快速版本，其可预测性与原始方法相同。我们发现，用半乳糖替换培养基中的葡萄糖导致HepG2细胞立即将它们的能量代谢从糖酵解转移到由于激烈的能量饥饿引起的氧化磷酸化;此外，当培养基中的葡萄糖被半乳糖替换时，通过尿毒剂减少ATP的细胞内浓度。使用我们提出的快速方法，可以通过药暴露在没有预培养步骤的情况下通过药物暴露来评估HepG2细胞中的线粒体功能障碍。对于线粒体毒性的这种快速测定可能比药物发育早期的原始方法更适合于高通量筛选。

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