title: Proteomic characterization of the possible molecular targets of pyrrolizidine alkaloid isoline-induced hepatotoxicity.
abstract: Pyrrolizidine alkaloids (PAs) are distributed in plants worldwide including medicinal herbs or teas. In the present study, we investigated the effects of isoline, which is a retronecine-type PA isolated from traditional Chinese medicinal herb Ligularia duciformis, on mouse liver proteins by using proteomic approaches. Firstly, our results showed that 110mg/kg isoline increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities in serum, and hepatic tissue pathological observation further confirmed isoline-induced liver injury. Proteomic analysis showed that the liver samples from mice of isoline group demonstrated about 13 differentially expressed proteins compared with normal group, and those proteins may be involved in isoline-induced liver injury in mice. Next, all these 13 protein spots were identified by MALDI-TOF-TOF MS or LTQ MS; and among them 9 differentially expressed proteins are involved in the process of oxidative stress or cellular energy metabolism. Further lipid peroxidation analysis and ATPase assay confirmed the existing of oxidative injury induced by isoline and consequent disruption of energy metabolism. Furthermore, an in silico drug target searching program INVDOCK identified 2 potential protein targets of isoline, and the results are in support of proteomic analysis. In summary, the possible signaling molecules related with isoline-induced liver injury were demonstrated in this study.
authors.affiliation: The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, 201210, China.
authors.forename: Zai-Yong
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Kang
authors.affiliation: The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, 201210, China. Electronic address: lily0913@yahoo.cn.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Ji
authors.affiliation: Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
authors.forename: Yong-Qing
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China.
authors.forename: Tian-Yu
authors.initials: TY
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Cao
authors.affiliation: Western Australian Institute for Medical Research, the University of Western Australia, Perth WA 6000, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Morahan
authors.affiliation: The MOE Key Laboratory for Standardization of Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201210, China; Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, 201210, China. Electronic address: wangzht@hotmail.com.
authors.forename: Zheng-Tao
authors.initials: ZT
authors.lastname: Wang
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D019659:Asteraceae; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D015180:Electrophoresis, Gel, Two-Dimensional; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D040901:Proteomics; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
chemical_list: D011763:Pyrrolizidine Alkaloids; C489556:isoline; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000251:Adenosine Triphosphatases