title: Increased serum bile acid concentration following low-dose chronic administration of thioacetamide in rats, as evidenced by metabolomic analysis.
abstract: A liquid chromatography/time-of-flight mass spectrometry (LC/TOF-MS)-based metabolomics approach was employed to identify endogenous metabolites as potential biomarkers for thioacetamide (TAA)-induced liver injury. TAA (10 and 30mg/kg), a well-known hepatotoxic agent, was administered daily to male Sprague-Dawley (SD) rats for 28days. We then conducted untargeted analyses of endogenous serum and liver metabolites. Partial least squares discriminant analysis (PLS-DA) was performed on serum and liver samples to evaluate metabolites associated with TAA-induced perturbation. TAA administration resulted in altered levels of bile acids, acyl carnitines, and phospholipids in serum and in the liver. We subsequently demonstrated and confirmed the occurrence of compromised bile acid homeostasis. TAA treatment significantly increased serum levels of conjugated bile acids in a dose-dependent manner, which correlated well with toxicity. However, hepatic levels of these metabolites were not substantially changed. Gene expression profiling showed that the hepatic mRNA levels of Ntcp, Bsep, and Oatp1b2 were significantly suppressed, whereas those of basolateral Mrp3 and Mrp4 were increased. Decreased levels of Ntcp, Oatp1b2, and Ostα proteins in the liver were confirmed by western blot analysis. These results suggest that serum bile acids might be increased due to the inhibition of bile acid enterohepatic circulation rather than increased endogenous bile acid synthesis. Moreover, serum bile acids are a good indicator of TAA-induced hepatotoxicity.
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735, Republic of Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735, Republic of Korea.
authors.forename: Gabin
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735, Republic of Korea.
authors.forename: Ho Jung
authors.initials: HJ
authors.lastname: Shin
authors.affiliation: Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors.forename: Se-Myo
authors.initials: SM
authors.lastname: Park
authors.affiliation: Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors.forename: Yong-Bum
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, Republic of Korea.
authors.forename: Kyoung-Sik
authors.initials: KS
authors.lastname: Moon
authors.affiliation: College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea.
authors.forename: Hyung-Kyoon
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Ministry of Food and Drug Safety, Osong-eup, Heungdeok-gu, Cheongju-si, Chungcheongbuk-do 361-951, Republic of Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Jeong
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735, Republic of Korea.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
authors.affiliation: Department of Pharmacology and Pharmacogenomics Research Center, Inje University, College of Medicine, Bokjiro 75, Busanjin-Gu, Busan 614-735, Republic of Korea. Electronic address: dhkim@inje.ac.kr.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood* / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004764:Enterohepatic Circulation; D020869:Gene Expression Profiling; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D055432:Metabolomics / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D013853:Thioacetamide / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D013853:Thioacetamide
keywords: Bile acids; Enterohepatic circulation; Hepatotoxicity; Metabolomics; Thioacetamide; Transporter