title: Comprehensive analysis of hepatic gene and protein expression profiles on phenobarbital- or clofibrate-induced hepatic hypertrophy in dogs.
abstract: In order to characterize the hepatic effects of phenobarbital (PB) and clofibrate (CPIB) in dogs, PB and CPIB were administered to male beagle dogs for 14 days, and biochemical and histopathological examinations and comprehensive genomic and proteomic analyses, including GeneChip analysis and proteomics analysis using the 2-dimension difference gel electrophoresis (2D-DIGE) technique, were performed. Both compounds caused centrilobular hepatocellular hypertrophy, which were related to smooth endoplasmic reticulum (SER) proliferation in PB-treated dogs and to mitochondrial proliferation in CPIB-treated dogs. In the PB-treated dogs, drug-metabolizing enzyme induction was observed by Western blot and genomic analyses. CYP proteins could not be detected by the 2D-DIGE analysis, but increases in several endoplasmic reticulum (ER)-related proteins were observed. In the CPIB-treated dogs, drug-metabolizing enzyme induction was not clearly observed by any of Western blot, genomic and proteomic analyses. Genomic and proteomic analyses revealed that mitochondrial genes and proteins, including carnitine palmytoiltransferase II, acyl-CoA deheydrogenase and hydroxyacyl-CoA dehydrogenase, pyruvate carboxylase and ATP synthase beta chain were induced. There is a relatively good correlation among the morphology and the genomic and proteomic data, but some differences exist between the genomic and proteomic data. Comprehensive evaluation using these techniques in addition to morphological evaluation may provide a useful tool for safety assessment of the liver.
authors: Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Shizuoka, Japan. makino.toshihiko.f7@daiichisankyo.co.jp
authors: Toshihiko
authors: T
authors: Makino
authors: Junzo
authors: J
authors: Kinoshita
authors: Shingo
authors: S
authors: Arakawa
authors: Kazumi
authors: K
authors: Ito
authors: Yosuke
authors: Y
authors: Ando
authors: Takashi
authors: T
authors: Yamoto
authors: Munehiro
authors: M
authors: Teranishi
authors: Atsushi
authors: A
authors: Sanbuissho
authors: Hiroyuki
authors: H
authors: Nakayama
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000378:metabolism; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002994:Clofibrate; D004285:Dogs; D015180:Electrophoresis, Gel, Two-Dimensional; D018871:Endoplasmic Reticulum, Smooth; D006529:Hepatomegaly / Q000139:chemically induced*; D008099:Liver / Q000166:cytology / Q000648:ultrastructure; D008297:Male; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010634:Phenobarbital; D040901:Proteomics
chemical_list: D042964:Acyl-CoA Dehydrogenase; D002334:Carnitine O-Palmitoyltransferase; D002994:Clofibrate; D010634:Phenobarbital