title: Metabolomic and genomic evidence for compromised bile acid homeostasis by senecionine, a hepatotoxic pyrrolizidine alkaloid.
abstract: Pyrrolizidine alkaloids (PAs) are among the most hepatotoxic natural products that produce irreversible injury to humans via the consumption of herbal medicine and honey, and through tea preparation. Toxicity and death caused by PA exposure have been reported worldwide. Metabolomics and genomics provide scientific and systematic views of a living organism and have become powerful techniques for toxicology research. In this study, senecionine hepatotoxicity on rats was determined via a combination of metabolomic and genomic analyses. From the global analysis generated from two omics data, the compromised bile acid homeostasis in vivo was innovatively demonstrated and confirmed. Serum profiling of bile acids was altered with significantly elevated conjugated bile acids after senecionine exposure, which was in accordance with toxicity. Similarly, the hepatic mRNA levels of several key genes associated with bile acid metabolism were significantly changed. This process included cholesterol 7-α hydroxylase, bile acid CoA-amino acid N-acetyltransferase, sodium taurocholate cotransporting polypeptide, organic anion-transporting polypeptides, and multidrug-resistance-associated protein 3. In conclusion, a cross-omics study provides a comprehensive analysis method for studying the toxicity caused by senecionine, which is a hepatotoxic PA. Moreover, the change in bile acid metabolism and the respective transporters may provide a new PA toxicity mechanism.
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 , 1200 Cailun Road, Shanghai 201203, China.
authors.forename: Aizhen
authors.initials: A
authors.lastname: Xiong
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Lianxiang
authors.initials: L
authors.lastname: Fang
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Yuqi
authors.initials: Y
authors.lastname: He
authors.forename: Yu-Jui Yvonne
authors.initials: YJ
authors.lastname: Wan
authors.forename: Yvonne Yu-Jui
authors.initials: YY
authors.lastname: Wan
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Meng
authors.initials: M
authors.lastname: Qi
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.forename: Kate
authors.initials: K
authors.lastname: Yu
authors.forename: Karl Wah-Keung
authors.initials: KW
authors.lastname: Tsim
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D023281:Genomics / Q000379:methods; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D055432:Metabolomics / Q000379:methods; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001647:Bile Acids and Salts; D011763:Pyrrolizidine Alkaloids; D012333:RNA, Messenger; C009237:senecionine