Yao Yiran, Zhang Pei, Wang Jing, Chen Jiaqing, Wang Yong, Huang Yin, Zhang Zunjian, Xu Fengguo
Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical UniversityNanjing, China; Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical UniversityNanjing, China; State Key Laboratory of Natural Medicine, China Pharmaceutical UniversityNanjing, China.
School of Pharmacy, Shanxi University of Chinese Medicine Xianyang, China.
Front Pharmacol. 2017 Mar 10;8:122. doi: 10.3389/fphar.2017.00122. eCollection 2017.
As an anticancer agent, irinotecan (CPT-11) has been widely applied in clinical, especially in the treatment of colorectal cancer. However, its clinical use has long been limited by the side effects and potential tissue toxicity. To discriminate the target toxic tissues and dissect the specific response of target tissues after CPT-11 administration in rats, untargeted metabolomic study was conducted. First, differential metabolites between CPT-11 treated group and control group in each tissue were screened out. Then, based on fold changes of these differential metabolites, principal component analysis and hierarchical cluster analysis were performed to visualize the degree and specificity of the influences of CPT-11 on the metabolic profiles of nine tissues. Using this step-wise method, ileum, jejunum, and liver were finally recognized as target toxic tissues. Furthermore, tissue specific responses of liver, ileum, and jejunum to CPT-11 were dissected and specific differential metabolites were screened out. Perturbations in Krebs cycle, amino acid, purine and bile acid metabolism were observed in target toxic tissues. In conclusion, our study put forward a new approach to dissect target toxic tissues and tissue specific responses of CPT-11 using metabolomics.
作为一种抗癌药物，伊立替康（CPT - 11）已在临床上广泛应用，尤其是在结直肠癌的治疗中。然而，其临床应用长期以来受到副作用和潜在组织毒性的限制。为了鉴别大鼠给予CPT - 11后的靶毒性组织并剖析靶组织的特异性反应，进行了非靶向代谢组学研究。首先，筛选出CPT - 11处理组与对照组各组织之间的差异代谢物。然后，基于这些差异代谢物的变化倍数，进行主成分分析和层次聚类分析，以直观呈现CPT - 11对九种组织代谢谱影响的程度和特异性。采用这种逐步方法，最终确定回肠、空肠和肝脏为靶毒性组织。此外，剖析了肝脏、回肠和空肠对CPT - 11的组织特异性反应，并筛选出特异性差异代谢物。在靶毒性组织中观察到三羧酸循环、氨基酸、嘌呤和胆汁酸代谢的扰动。总之，我们的研究提出了一种利用代谢组学剖析CPT - 11靶毒性组织和组织特异性反应的新方法。
