Wang Zhipeng, Liu Zhijun, Cui Lili, Sun Jianguo, Bu Chen, Tang Mao, Li Mingming, Gao Shouhong, Chen Wansheng, Tao Xia
Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR China.
Department of Pharmacy, Second Affiliated Hospital of Naval Medical University, Shanghai 200003, PR China; Research and Development Center of Chinese Medicine Resources and Biotechnology, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
J Adv Res. 2025 Jun;72:591-604. doi: 10.1016/j.jare.2024.07.019. Epub 2024 Jul 22.
Diarrhea is the primary dose-limiting side effect of capecitabine(Cap) hindering its clinical application, but the mechanism is unclear. Clarifying this mechanism may enhance the patient compliance and improve the treatment outcome.
To assess if the endogenous metabolic profile could prodict the diarrhea induced by Cap and explore and validate underlying mechanisms.
Untargeted and targeted bile acids(BAs) metabolomics were performed to analyzed the metabolic profile of baseline samples from colorectal cancer(CRC) patients and the association with the diarrhea induced by Cap was assessed. The toxicity of BAs and Cap and its metabolites alone or their combinations to the human normal intestinal epithelial cell(HIEC) was assessed, and the key genes that mediated the BAs-enhanced toxicity of Cap were discovered by RNA-seq and then validated. A mouse model with high exposure levels of BAs was constructed and then treated with Cap to verify the Cap-induced diarrhea enhanced by BAs.
The baseline endogenous metabolic profile showed obviously difference between diarrhea and non-diarrhea CRC patients, and the differential metabolites mainly enriched in BAs metabolism; the deoxycholic acid(DCA) and lithocholic acid(LCA) were selected to be the key BAs that enhanced the toxicity of Cap metabolite 5-FU to the HIEC cell; the DCA and LCA could inhibit the Wnt/β-catenin signaling pathway, which then suppressed the P-glycoprotein and increased the exposure level of 5-FU in the HIEC cell. The results of animal experiment verified that the excessive DCA and LCA could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.
The disordered BAs metabolic profile showed close relationship with diarrhea induced by Cap, and excessive DCA and LCA were proved to be the key BAs, which could aggravate the Cap-induced diarrhea through inhibiting Wnt/β-catenin-P-glycoprotein pathway.
腹泻是卡培他滨（Cap）的主要剂量限制性副作用，阻碍了其临床应用，但其机制尚不清楚。阐明这一机制可能会提高患者的依从性并改善治疗效果。
评估内源性代谢谱是否可预测卡培他滨引起的腹泻，并探索和验证潜在机制。
采用非靶向和靶向胆汁酸（BAs）代谢组学分析结直肠癌（CRC）患者基线样本的代谢谱，并评估其与卡培他滨引起的腹泻的相关性。评估胆汁酸、卡培他滨及其代谢产物单独或联合对人正常肠上皮细胞（HIEC）的毒性，并通过RNA测序发现介导胆汁酸增强卡培他滨毒性的关键基因，然后进行验证。构建高胆汁酸暴露水平的小鼠模型，然后用卡培他滨治疗，以验证胆汁酸增强的卡培他滨诱导的腹泻。
腹泻和非腹泻CRC患者的基线内源性代谢谱存在明显差异，差异代谢物主要富集在胆汁酸代谢中；选择脱氧胆酸（DCA）和石胆酸（LCA）作为增强卡培他滨代谢物5-FU对HIEC细胞毒性的关键胆汁酸；DCA和LCA可抑制Wnt/β-连环蛋白信号通路，进而抑制P-糖蛋白并增加HIEC细胞中5-FU的暴露水平。动物实验结果证实，过量的DCA和LCA可通过抑制Wnt/β-连环蛋白-P-糖蛋白途径加重卡培他滨诱导的腹泻。
胆汁酸代谢谱紊乱与卡培他滨引起的腹泻密切相关，过量的DCA和LCA被证明是关键胆汁酸，可通过抑制Wnt/β-连环蛋白-P-糖蛋白途径加重卡培他滨诱导的腹泻。
