title: Subchronic effects of valproic acid on gene expression profiles for lipid metabolism in mouse liver.
abstract: Valproic acid (VPA) is used clinically to treat epilepsy, however it induces hepatotoxicity such as microvesicular steatosis. Acute hepatotoxicity of VPA has been well documented by biochemical studies and microarray analysis, but little is known about the chronic effects of VPA in the liver. In the present investigation, we profiled gene expression patterns in the mouse liver after subchronic treatment with VPA. VPA was administered orally at a dose of 100 mg/kg/day or 500 mg/kg/day to ICR mice, and the livers were obtained after 1, 2, or 4 weeks. The activities of serum liver enzymes did not change, whereas triglyceride concentration increased significantly. Microarray analysis revealed that 1325 genes of a set of 32,996 individual genes were VPA responsive when examined by two-way ANOVA (P<0.05) and fold change (>1.5). Consistent with our previous results obtained using an acute VPA exposure model (Lee et al., Toxicol Appl Pharmacol. 220:45-59, 2007), the most significantly over-represented biological terms for these genes included lipid, fatty acid, and steroid metabolism. Biological pathway analysis suggests that the genes responsible for increased biosynthesis of cholesterol and triglyceride, and for decreased fatty acid beta-oxidation contribute to the abnormalities in lipid metabolism induced by subchronic VPA treatment. A comparison of the VPA-responsive genes in the acute and subchronic models extracted 15 commonly altered genes, such as Cyp4a14 and Adpn, which may have predictive power to distinguish the mode of action of hepatotoxicants. Our data provide a better understanding of the molecular mechanisms of VPA-induced hepatotoxicity and useful information to predict steatogenic hepatotoxicity.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Lee
authors.forename: Mingoo
authors.initials: M
authors.lastname: Kim
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
authors.forename: Ju-Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
authors.forename: Hyung-Lae
authors.initials: HL
authors.lastname: Kim
authors.forename: Byung-Il
authors.initials: BI
authors.lastname: Yoon
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Chung
authors.forename: Gu
authors.initials: G
authors.lastname: Kong
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D012333:RNA, Messenger; D014280:Triglycerides; D014635:Valproic Acid