Metabolomics Study With Gas Chromatography-Mass Spectrometry for Predicting Valproic Acid-induced Hepatotoxicity and Discovery of Novel Biomarkers in Rat Urine
- Authors
- Lee, Min Sun; Jung, Byung Hwa; Chung, Bong Chul; Cho, Sung Hee; Kim, Ki Young; Kwon, Oh Seoung; Nugraha, Boya; Lee, Young-Joo
- Issue Date
- 2009-09
- Publisher
- SAGE PUBLICATIONS INC
- Citation
- INTERNATIONAL JOURNAL OF TOXICOLOGY, v.28, no.5, pp.392 - 404
- 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.
- Keywords
- GLUTATHIONE-S-TRANSFERASE; SWITCHING LIQUID-CHROMATOGRAPHY; QUANTITATIVE-DETERMINATION; HEPATOCELLULAR-DAMAGE; LIPID-PEROXIDATION; OXIDATIVE DAMAGE; CARNITINE; PLASMA; LIVER; DNA; valproic acid; hepatotoxicity; metabolic profiling; metabolomics; gas chromatography-mass spectrometry
- ISSN
- 1091-5818
- URI
- https://pubs.kist.re.kr/handle/201004/132191
- DOI
- 10.1177/1091581809340329
- Appears in Collections:
- KIST Article > 2009
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