BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Republic of Korea.
College of Pharmacy, Chosun University, Gwangju 61452, Republic of Korea.
Toxicol Appl Pharmacol. 2018 Aug 1;352:28-37. doi: 10.1016/j.taap.2018.05.021. Epub 2018 May 21.
Non-alcoholic fatty liver disease (NAFLD) includes conditions such as steatosis, non-alcoholic steatohepatitis, and ultimately hepatocellular carcinoma. Although the pathology of NAFLD is well-established, NAFLD-induced drug metabolism mediated by cytochrome P450 (CYP) in the liver has remained largely unexplored. Therefore, we investigated NAFLD-induced drug metabolism mediated by CYP by quantitative toxicoproteomics analysis. After administration of a methionine-choline deficient (MCD) diet to induce development of NAFLD, tandem mass tags-based liquid chromatography-tandem mass spectrometry analysis was conducted to investigate the dynamics of hepatic proteins. A total of 1295 proteins were identified, of which 934 were quantified by proteomic analysis. Among these proteins, 21 proteins were up-regulated and 51 proteins were down-regulated by the MCD diet. Notably, domain annotation enrichment using InterPro indicated that proteins related to CYPs were significantly decreased. When we investigated CYP activity using in vivo and in vitro CYP cocktail assays, most CYPs were significantly decreased, whereas CYP2D was not changed after administration of the MCD diet. In conclusion, we identified significantly altered levels of CYPs and their activities induced by the MCD diet and confirmed the NAFLD-induced drug metabolism by pharmacokinetic analysis.
非酒精性脂肪性肝病（NAFLD）包括脂肪变性、非酒精性脂肪性肝炎等病症，最终可发展为肝细胞癌。尽管 NAFLD 的病理学已得到充分证实，但肝脏细胞色素 P450（CYP）介导的 NAFLD 诱导的药物代谢仍在很大程度上未被探索。因此，我们通过定量毒理学蛋白质组学分析来研究 CYP 介导的 NAFLD 诱导的药物代谢。通过给予蛋氨酸-胆碱缺乏（MCD）饮食来诱导 NAFLD 的发展后，进行基于串联质量标签的液相色谱-串联质谱分析，以研究肝蛋白质的动态变化。共鉴定到 1295 种蛋白质，其中 934 种通过蛋白质组学分析进行了定量。在这些蛋白质中，MCD 饮食上调了 21 种蛋白质，下调了 51 种蛋白质。值得注意的是，使用 InterPro 进行的结构域注释富集表明，与 CYP 相关的蛋白质显著减少。当我们使用体内和体外 CYP 鸡尾酒测定法研究 CYP 活性时，大多数 CYP 显著降低，而 MCD 饮食给药后 CYP2D 没有变化。总之，我们鉴定了 MCD 饮食诱导的 CYP 及其活性的显著改变水平，并通过药代动力学分析证实了 NAFLD 诱导的药物代谢。
