title: Integrated systems toxicology approaches identified the possible involvement of ABC transporters pathway in erythromycin estolate-induced liver injury in rat.
abstract: Erythromycin estolate (EE), a macrolide antibiotic, has caused hepatotoxicity both in human and experimental animals. The objective of this study was to integrate general toxicology, transcriptomics, and metabonomics approaches to determine the mechanisms of EE-induced liver injury. Histopathological examinations unveiled dose-dependent hydropicdegenerationof hepatocytes after EE administration. Further biochemical analysis of treated rats confirmed that cholestasis and oxidative stress were induced by EE treatments. Microarray analysis of the livers from EE-treated rats showed that differentially expressed genes were enriched in the ABC transporters, cell cycle, and p53 signaling pathways. Metabonomics analysis revealed that EE exposure could lead to disturbances in energy metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism, which may be attributable to EE toxicological effects on the liver through oxidative stress. 5-Oxoproline may be used as a biomarker of EE-induced liver injury. More importantly, the integrated analysis of transcriptomics and metabonomics datasets demonstrated that the induction of ABC transporters pathway severed as an anti-cholestatic adaptive mechanism in EE-induced cholestasis. In addition, EE-induced liver injury was also related to alteration in glycogen and sucrose metabolism, arachidonic acid metabolism, and linoleic acid metabolism pathways.
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Lu
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Lian
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yachao
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Jin
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.affiliation: Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Shen
authors.affiliation: Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: fanxh@zju.edu.cn.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Fan
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004918:Erythromycin Estolate / Q000633:toxicity*; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018528:ATP-Binding Cassette Transporters; D004918:Erythromycin Estolate
keywords: ABC transporters pathway; Cholestasis; Erythromycin estolate; Metabonomics; Oxidative stress; Transcriptomics