title: Metabolomics study with gas chromatography-mass spectrometry for predicting valproic acid-induced hepatotoxicity and discovery of novel biomarkers in rat urine.
abstract: Three different doses of valproic acid (20, 100, and 500 mg/kg/d) are administered orally to Sprague-Dawley rats for 5 days, and the feasibility of metabolomics with gas chromatography-mass spectrometry as a predictor of the hepatotoxicity of valproic acid is evaluated. Body weight is found to decrease with the 100-mg/kg/d dose and significantly decrease with the 500-mg/kg/d dose. Mean excreted urine volume is lowest in the 500-mg/kg/d group among all groups. The plasma level of alpha-glutathione-S-transferase, a sensitive and earlier biomarker for hepatotoxicity, increases significantly with administration of 100 and 500 mg/kg/d; however, there is not a significant difference in alpha-glutathione-S-transferase plasma levels between the control and 20-mg/kg/d groups. Clusters in partial least squares discriminant analysis score plots show similar patterns, with changes in physiological conditions and plasma levels of alpha-glutathione-S-transferase; the cluster for the control and 20-mg/kg/d groups does not clearly separate, but the clusters are separate for 100- and 500-mg/kg/d groups. A biomarker of hepatotoxicity, 8-hydroxy-2'-deoxyguanosine and octanoylcarnitine, is identified from nontargeted and targeted metabolic profiling. These results validate that metabolic profiling using gas chromatography-mass spectrometry could be a useful tool for finding novel biomarkers. Thus, a nontargeted metabolic profiling method is established to evaluate the hepatotoxicity of valproic acid and demonstrates proof-of-concept that metabolomic approach with gas chromatography-mass spectrometry has great potential for predicting valproic acid-induced hepatotoxicity and discovering novel biomarkers.
authors: Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Cheongryang, Seoul, South Korea. jbhluck@kist.re.kr
authors: Min Sun
authors: MS
authors: Lee
authors: Byung Hwa
authors: BH
authors: Jung
authors: Bong Chul
authors: BC
authors: Chung
authors: Sung Hee
authors: SH
authors: Cho
authors: Ki Young
authors: KY
authors: Kim
authors: Oh Seoung
authors: OS
authors: Kwon
authors: Boya
authors: B
authors: Nugraha
authors: Young-Joo
authors: YJ
authors: Lee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000633:toxicity*; D015415:Biomarkers / Q000652:urine*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology / Q000652:urine*; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry; D005982:Glutathione Transferase / Q000097:blood; D016018:Least-Squares Analysis; D008297:Male; D055432:Metabolomics / Q000379:methods*; D015394:Molecular Structure; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D015415:Biomarkers; D014635:Valproic Acid; D005982:Glutathione Transferase