Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, South Korea.
College of Pharmacy, Chung-Ang University, Seoul, South Korea.
J Appl Toxicol. 2020 Jul;40(7):1004-1013. doi: 10.1002/jat.3960. Epub 2020 Feb 21.
Amiodarone is known to induce hepatic injury in some recipients. We applied an untargeted metabolomics approach to identify endogenous metabolites with potential as biomarkers for amiodarone-induced liver injury. Oral amiodarone administration for 1 week in rats resulted in significant elevation of acylcarnitines and phospholipids in the liver. Hepatic short- and medium-chain acylcarnitines were dramatically increased in a dose-dependent manner, while the serum levels of these acylcarnitines did not change substantially. In addition, glucose levels were significantly increased in both the serum and liver. Gene expression profiling showed that the hepatic mRNA levels of Cpt1, Cpt2, and Acat1 were significantly suppressed, whereas those of Acot1, Acly, Acss2, and Acsl3 were increased. These results suggest that hepatic acylcarnitines and glucose levels might be increased due to disruption of mitochondrial function and suppression of glucose metabolism. Perturbation of energy metabolism might be associated with amiodarone-induced hepatotoxicity.
胺碘酮已知可在一些受者中引起肝损伤。我们应用非靶向代谢组学方法来鉴定可能作为胺碘酮诱导的肝损伤生物标志物的内源性代谢物。在大鼠中给予胺碘酮口服治疗 1 周导致肝脏酰基辅酶 A 和磷脂的显著升高。肝短链和中链酰基辅酶 A 呈剂量依赖性显著增加，而这些酰基辅酶 A 的血清水平没有显著变化。此外，血清和肝脏中的葡萄糖水平均显著升高。基因表达谱显示，肝 Cpt1、Cpt2 和 Acat1 的 mRNA 水平显著受抑制，而 Acot1、Acly、Acss2 和 Acsl3 的 mRNA 水平增加。这些结果表明，由于线粒体功能障碍和葡萄糖代谢抑制，肝酰基辅酶 A 和葡萄糖水平可能升高。能量代谢的紊乱可能与胺碘酮诱导的肝毒性有关。
