Wang Haina, Fang Zhong-Ze, Meng Ran, Cao Yun-Feng, Tanaka Naoki, Krausz Kristopher W, Gonzalez Frank J
School of Pharmaceutical Sciences, Shandong University, Jinan, 250012, PR China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States; Department of Toxicology, School of Public Health, Tianjin Medical University, Heping District, Tianjin, 300070, PR China; Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, PR China.
Toxicology. 2017 Jul 1;386:133-142. doi: 10.1016/j.tox.2017.05.012. Epub 2017 May 24.
Alpha-naphthyl isothiocyanate (ANIT) is a common hepatotoxicant experimentally used to reproduce the pathologies of drug-induced liver injury in humans, but the mechanism of its toxicity remains unclear. To determine the metabolic alterations following ANIT exposure, metabolomic analyses was performed by use of liquid chromatography-mass spectrometry. Partial least squares discriminant analysis (PLS-DA) of liver, serum, bile, ileum, and cecum of vehicle- and ANIT-treated mice revealed significant alterations of individual bile acids, including increased tauroursodeoxycholic acid, taurohydrodeoxycholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid, and decreased ω-, β- and tauro-α/β- murideoxycholic acid, cholic acid, and taurocholic acid in the ANIT-treated groups. In accordance with these changes, ANIT treatment altered the expression of mRNAs encoded by genes responsible for the metabolism and transport of bile acids and cholesterol. Pre-treatment of glycyrrhizin (GL) and glycyrrhetinic acid (GA) prevented ANIT-induced liver damage and reversed the alteration of bile acid metabolites and Cyp7a1, Npc1l1, Mttp, and Acat2 mRNAs encoding bile acid transport and metabolism proteins. These results suggested that GL/GA could prevent drug-induced liver injury and ensuing disruption of bile acid metabolism in humans.
α-萘基异硫氰酸酯（ANIT）是一种常见的肝毒性物质，在实验中用于重现人类药物性肝损伤的病理情况，但其毒性机制仍不清楚。为了确定ANIT暴露后的代谢变化，采用液相色谱-质谱联用技术进行了代谢组学分析。对用载体和ANIT处理的小鼠的肝脏、血清、胆汁、回肠和盲肠进行偏最小二乘判别分析（PLS-DA），结果显示个别胆汁酸有显著变化，包括在ANIT处理组中牛磺熊去氧胆酸、牛磺氢脱氧胆酸、牛磺鹅去氧胆酸和牛磺脱氧胆酸增加，而ω-、β-和牛磺-α/β-鼠李脱氧胆酸、胆酸和牛磺胆酸减少。与这些变化一致，ANIT处理改变了负责胆汁酸和胆固醇代谢及转运的基因所编码的mRNA的表达。甘草酸（GL）和甘草次酸（GA）预处理可预防ANIT诱导的肝损伤，并逆转胆汁酸代谢产物以及编码胆汁酸转运和代谢蛋白的Cyp7a1、Npc1l1、Mttp和Acat2 mRNA的改变。这些结果表明，GL/GA可预防人类药物性肝损伤及随之而来的胆汁酸代谢紊乱。
