This Article Full Text Full Text (PDF) All Versions of this Article: 1091581809340329v1 28/5/392    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Add to My Marked Citations Citing Articles Citing Articles via Scopus Google Scholar Articles by Lee, M. S. Articles by Lee, Y.-J. PubMed PubMed Citation Articles by Lee, M. S. Articles by Lee, Y.-J. Social Bookmarking                         What's this?

Metabolomics Study With Gas Chromatography–Mass Spectrometry for Predicting Valproic Acid–induced Hepatotoxicity and Discovery of Novel Biomarkers in Rat Urine

From the Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul, Korea, (MSL, BHJ, BCC, SHC, KYK, OSK, BN); and the College of Pharmacy, Kyung Hee University, Seoul, Korea, (KYK, YJL).

Correspondence: Byung Hwa Jung, PhD, Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul, South Korea, 130-650; e-mail: jbhluck{at}kist.re.kr.

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 -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 -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 -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.

Key Words: valproic acid • hepatotoxicity • metabolic profiling • metabolomics • gas chromatography–mass spectrometry

This version was published on September 1, 2009

International Journal of Toxicology, Vol. 28, No. 5, 392-404 (2009)
DOI: 10.1177/1091581809340329


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?