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	H-1 NMR-based metabolomic analysis of triptolide-induced toxicity in liver-specific cytochrome P450 reductase knockout mice
	Liu, Xia ; Xue, Xiang ; Gong, Likun ; Qi, Xinming ; Wu, Yuanfeng ; Xing, Guozhen ; Luan, Yang ; Xiao, Ying ; Wu, Xiongfei ; Li, Yan ; Chen, Min ; Miao, Lingling ; Yao, Jun ; Gu, Jun ; Lin, Donghai ; Ren, Jin
	2012-10
关键词	Metabolomics Triptolide Toxicity Cytochrome P450 Hepatotoxicity
英文摘要	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 H-1 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.; National Grand Fundamental Research 973 Program of China [2006CB504700, 2007CB914304]; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China [2009ZX09301-001, 2008ZX09305-007, 2009ZX09501-033]; Program of Shanghai Subject Chief Scientist [09XD1405100]
语种	英语
出版者	SPRINGER
内容类型	期刊论文
源URL	[http://dx.doi.org/10.1007/s11306-011-0385-1]
专题	化学化工－已发表论文
推荐引用方式 GB/T 7714	Liu, Xia,Xue, Xiang,Gong, Likun,et al. H-1 NMR-based metabolomic analysis of triptolide-induced toxicity in liver-specific cytochrome P450 reductase knockout mice[J],2012.
APA	Liu, Xia.,Xue, Xiang.,Gong, Likun.,Qi, Xinming.,Wu, Yuanfeng.,...&Ren, Jin.(2012).H-1 NMR-based metabolomic analysis of triptolide-induced toxicity in liver-specific cytochrome P450 reductase knockout mice..
MLA	Liu, Xia,et al."H-1 NMR-based metabolomic analysis of triptolide-induced toxicity in liver-specific cytochrome P450 reductase knockout mice".(2012).

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