基于脂肪酸代谢轮廓分析川楝子的肝毒性研究

Evaluation of Toosendan Fructus-induced hepatotoxicity based on metabolic profile of fatty acids

目的从脂肪酸代谢轮廓的角度评价川楝子(TF)水提醇沉物和川楝子+延胡索(TF+CR)水提醇沉物的小鼠肝毒性。方法采用气相-质谱联用技术定量分析对照组、TF组和TF+CR组小鼠血清中15种游离脂肪酸和酯化脂肪酸,结合化学计量学方法分析小鼠给药后脂肪酸代谢轮廓的变化和生物标识物。结果血清脂肪酸定量测定结果经主成分分析表明TF给药后小鼠的血清脂肪酸代谢轮廓明显偏离正常水平,而具有保肝作用的CR可逆转这种偏离;偏最小二乘法-判别分析表明棕榈油酸、十八碳烯酸和花生四烯酸对表征TF小鼠肝毒性具有重要贡献,可作为评价TF肝毒性的生物标识物。结论 TF肝毒性与脂肪酸的代谢轮廓密切相关。

Objective To evaluate the hepatotoxicity caused by water extract with alcohol precipitating of Toosendan Fructus（TF） and Toosendan Fructus ＋ Corydalis Rhizoma（TF ＋ CR） based on metabolic profiling of fatty acids in mice serum. Methods A gas chromatography-mass spectrometry method was applied for simultaneous quantification of 15 fatty acids, including both non-esterified and esterified fatty acids, in the serum of control, TF-treated, and TF ＋ CR-treated mice. Meanwhile, the change of fatty acid metabolic profile in liver injured mice was analyzed by principal component analysis（PCA） and partial least squares-discriminant analysis（PLS-DA）. ResultsThe result of PCA showed that the metabolic profile of serum fatty acids in TF-treated mice significantly deviated from the normal level, and CR with hepatoprotective effect could obviously reverse the deviation. More importantly, the result of PLS-DA illustrated that palmitoleic acid, vaccenic acid, and arachidonic acid had important contribution on the hepatotoxicity induced by TF. Therefore, the three fatty acids were identified as potential biomarkers. Conclusion Hepatotoxicity caused by TF has a good correlation with the metabolic profiling of fatty acid. The project can provide foundation for further investigation on the evaluation and mechanism of TF-induced hepatotoxicity.