Dissecting Target Toxic Tissue and Tissue Specific Responses of Irinotecan in Rats Using Metabolomics Approach.
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.
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.
Yiran
Y
Yao
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.
Pei
P
Zhang
School of Pharmacy, Shanxi University of Chinese Medicine Xianyang, China.
Jing
J
Wang
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.
Jiaqing
J
Chen
Jiangsu Institute for Food and Drug Control Nanjing, China.
Yong
Y
Wang
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.
Yin
Y
Huang
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.
Zunjian
Z
Zhang
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.
Fengguo
F
Xu
CPT-11; ileum; jejunum; liver; metabolomics; tissue specificity