目的 评价甘草总黄酮对伊立替康致肠炎小鼠的药效学影响，采用代谢组学方法分析伊立替康致肠炎模型小鼠血浆内源性代谢物的变化，观察甘草总黄酮对差异性代谢物的调节作用，对甘草总黄酮减轻伊立替康胃肠道毒性的作用机制进行初步探索。方法 将C57BL/6小鼠随机分为对照组、模型组、阳性药（环丙沙星）组和甘草总黄酮组，ip伊立替康制备肠炎模型，通过体质量、结肠长度、病理观察评价甘草总黄酮减轻伊立替康胃肠道毒性的作用，同时采用GC-MS技术进行非靶向代谢组学研究，寻找伊立替康致肠炎小鼠血浆内变化的相关差异性代谢物，并使用MetaboAnalyst软件构建代谢通路，从代谢组学的角度评价甘草总黄酮对伊立替康的减毒效应。结果 甘草总黄酮可显著改善伊立替康给药后导致的小鼠体质量减轻、结肠变短及肠道损伤等现象，且有效地逆转了伊立替康导致的小鼠血浆代谢紊乱，主要包括脂肪酸代谢、氨基酸代谢及糖类代谢，显著回调了月桂酸、棕榈酸、亚油酸、油酸、α-亚麻酸、棕榈酸单甘油酯和油酸单甘油酯等7种中长链脂肪酸。结论 甘草总黄酮主要通过调节亚油酸及α-亚麻酸代谢起到减轻伊立替康胃肠道毒性作用。

Objective To make a preliminary investigation on the mechanism of the glycyrrhizin flavonoids alleviating the gastrointestinal toxicities of irinotecan. The pharmacological effects of glycyrrhizin flavonoids on the changes of endogenous differential metabolites of irinotecan-induced gastrointestinal toxicities were evaluated by using GC-MS metabolomics methods. Methods C57BL/6 mice were divided into normal group, model group, positive group (ciprofloxacin), and glycyrrhizin flavonoids group. Irinotecan induced colitis model were established in mice by intraperitoneally injected. The body weight, length of colon, and tissue sections were used to evaluate the effect of glycyrrhizin flavonoids on alleviating irinotecan-induced experimental colitis. Meanwhile, to evaluate the attenuating effect of glycyrrhizin flavonoids from the perspective of metabonomics, GC-MS was used for non-targeted metabolism in order to find out the the change of related metabolites in plasma between experimental colitis mice and glycyrrhizin flavonoids treatment mice. Furthermore, metabolic pathway was constructed by MetaboAnalyst software to explore the potential mechanism. Results Glycyrrhizin flavonoids could significantly reduce the loss of body weight, colon shortening, and intestinal damage caused by irinotecan administration, and effectively reverse the irinotecan-induced plasma metabolic disorders in mice, including fatty acid metabolism, amino acid metabolism and carbohydrate metabolism, significantly callback seven long-chain fatty acids such as lauric acid, palmitic acid, linoleic acid, oleic acid, linolenic acid, palmitic acid monoglyceride, and oleic acid monoglyceride. Conclusion Glycyrrhizin flavonoids could improve the irinotecan-induced experimental colitis in mice by regulating linoleic acid metabolism and alpha-linolenic acid metabolism.

江苏省自然科学基金面上项目（BK20171497）；江苏省高校自然科学基金面上项目（16KJB360005）