Abstract
Metabolomics allows high-throughput analysis of low-molecular-weight compounds in biofluids that reflect the physiological status and biochemical metabolism of living systems. Hence it has the potential to evaluate toxicity and clarifies the metabolism-related toxic mechanisms. In this study a promising candidate drug parent, triptolide, was given to Sprague–Dawley rats as a model toxicant at a single dose of 0.6, or 2.4 mg/kg, i.g. Both routine biochemical assays and histopathological inspection showed time-dependent hepatic toxicity at the higher dose, but no obvious toxicity at the lower dose. Meanwhile, serum metabolome was profiled using the non-targeted metabolomic tool, gas chromatography time-of-flight mass spectrometry. Based on the acquired metabolomic data, mathematical models were calculated and the metabolic patterns of serum were evaluated using projection to latent structure-discriminant analysis. The relative distance of each treated group from the normal control was calculated to provide a measure of toxicity. Treatment with triptolide at either the higher or lower dose caused deviations in the metabolic pattern and resulted in perturbation of taurine, creatinine, free fatty acids, β-hydroxybutyrate, tricarboxylic acid cycle intermediates, and amino acids. This finding indicates the dysfunction of β-oxidation of free fatty acids and impairment of the mitochondria and confirms the hepatic toxicity of triptolide. The identified toxic markers and the calculated relative distance values quantitatively demonstrated dose- and time-dependent toxicity, whereas the scores plot of the model provided the qualitative information. The metabolomic approach was non-invasive and more sensitive than routine toxic assessment, and the results of both methods correlated well.
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Acknowledgments
This work was supported by the National Key New Drug Creation Special Programs (2009ZX09304-001 and 2009ZX09502-004), the Jiangsu Province Social Development Foundation (BE2008673), the Jiangsu Nature Science Fund (BK2008038) and the National 11th 5-Year Technology Supporting Program of the People’s Republic of China (No. 2006BAI08B04).
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Biochemical assays of Alanine aminotransferase (ALT), aspartate aminotransferase (AST), neutrophils (NE), and white blood cells (WBC) after exposure to triptolide (DOC 84 kb)
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Aa, J., Shao, F., Wang, G. et al. Gas chromatography time-of-flight mass spectrometry based metabolomic approach to evaluating toxicity of triptolide. Metabolomics 7, 217–225 (2011). https://doi.org/10.1007/s11306-010-0241-8
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DOI: https://doi.org/10.1007/s11306-010-0241-8