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.

中文翻译：

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甘草甜素和甘草次酸可抑制α-萘基异硫氰酸酯诱导的肝损伤和胆汁酸循环破坏。


α-萘基异硫氰酸酯（ANIT）是一种常见的肝毒性物质，实验上用于重现人类药物性肝损伤的病理，但其毒性机制仍不清楚。为了确定 ANIT 暴露后的代谢变化，利用液相色谱-质谱法进行代谢组学分析。对媒介物和 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)，结果显示个体胆汁酸发生显着变化，包括牛磺熊去氧胆酸、牛磺氢脱氧胆酸、牛磺鹅去氧胆酸和牛磺脱氧胆酸增加ANIT 治疗组中的 ω-、β- 和牛磺-α/β-鼠去氧胆酸、胆酸和牛磺胆酸减少。根据这些变化，ANIT 治疗改变了负责胆汁酸和胆固醇代谢和运输的基因编码的 mRNA 的表达。甘草酸 (GL) 和甘草次酸 (GA) 的预处理可预防 ANIT 诱导的肝损伤，并逆转胆汁酸代谢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 可以预防药物引起的肝损伤以及随之而来的人类胆汁酸代谢的破坏。