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1H NMR-based metabolomic analysis of triptolide-induced toxicity in liver-specific cytochrome P450 reductase knockout mice

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Abstract

Triptolide (TL) is an active component of Tripterygium wilfordii Hook. F which is used to treat autoimmune and inflammatory disease. However, a high incidence of adverse effects is often observed in clinic. Previously we have demonstrated that cytochrome P450s (CYPs) are involved in the metabolism of TL and low activity of hepatic P450 reductase aggravates TL-induced toxicity. However, the underlying mechanisms of TL-induced toxicity mediated by hepatic CYPs have not been well delineated. Here, an integrated 1H NMR-based metabolomic analysis was performed to evaluate the global biochemical alteration in the liver-specific cytochrome P450 reductase (CPR) knockout (KO) mice and wild-type (WT) counterparts with a same dose of TL (0.5 mg/kg) administration. Dramatically different metabolic profiles indicated more severe hepatotoxicity and nephrotoxicity induced by TL in KO mice than in WT mice, which were confirmed by serum biochemistry and histopathological examination. Furthermore, the results from both multivariate statistical analysis and system statistical metabolic correlation analysis indicated that the significantly changed endogenous metabolites were primarily involved in oxidative stress, energy metabolism, amino acid metabolism, gut microflora metabolism, and choline metabolism. Our results reveal the molecular mechanisms of TL-induced toxicity in the condition of hepatic CYP inactivation. As CYP inactivation and/or inhibition are usually caused by genetic polymorphism and/or drug–drug interactions, personalized prescription according to enzyme activity of CYPs and metabolic profiling could be used to maximize therapeutic efficacy and avoid or reduce TL-induced toxicity clinically.

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Acknowledgments

We thank Erik Anderson and Professor Yi-zheng Wang for proof-reading, Professor Wen-sen Wu for histopathology evaluation, Hua Sheng, Heng-lei Lu, Bei-yan Liu, Cheng Zheng and Jing Lu for technical assistance. This work was supported by National Grand Fundamental Research 973 Program of China (Nos. 2006CB504700, 2007CB914304), National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program”, China (Nos. 2009ZX09301-001, 2008ZX09305-007 and 2009ZX09501-033) and the Program of Shanghai Subject Chief Scientist (No. 09XD1405100).

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  1. Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Xiang Xue, Likun Gong, Xinming Qi, Yuanfeng Wu, Guozhen Xing, Yang Luan, Ying Xiao, Xiongfei Wu, Yan Li, Min Chen, Lingling Miao, Jun Yao & Jin Ren

  2. Biomolecular NMR Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Xia Liu

  3. The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China

    Donghai Lin

  4. Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, NY, USA

    Jun Gu

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  1. Xia Liu
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Correspondence to Donghai Lin or Jin Ren.

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Xia Liu and Xiang Xue contribute equally to this work.

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Liu, X., Xue, X., Gong, L. et al. 1H NMR-based metabolomic analysis of triptolide-induced toxicity in liver-specific cytochrome P450 reductase knockout mice. Metabolomics 8, 907–918 (2012). https://doi.org/10.1007/s11306-011-0385-1

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