Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

doi:10.1111/bph.14664

	Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity
	Zhao, Qi1,2 ; Zhang, Ting 1,2; Xiao, Xue-Rong 1; Huang, Jian-Feng 1,2; Wang, Yan 3; Gonzalez, Frank J.4; Li, Fei 1,5
通讯作者	Li, Fei(lifeib@mail.kib.ac.cn)
	2019-07-01
发表期刊	BRITISH JOURNAL OF PHARMACOLOGY
ISSN	0007-1188
卷号	176 期号:13 页码:2162-2178
摘要	Background and Purpose Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. Experimental Approach In the present study, mice were treated with 60, 150, and 450 mg center dot kg(-1) sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, faeces, and urine were analysed using ultra-performance LC electrospray ionization quadrupole time-of-flight MS-based metabolomics. Key Results Four reactive metabolites and impaired clearance of sunitinib in liver played a dominant role in sunitinib-induced hepatotoxicity. Using a non-targeted metabolomics approach, various metabolic pathways, including mitochondrial fatty acid beta-oxidation (beta-FAO), bile acids, lipids, amino acids, nucleotides, and tricarboxylic acid cycle intermediates, were disrupted after sunitinib treatment. Conclusions and Implications These studies identified significant alterations in mitochondrial beta-FAO and bile acid homeostasis. Activation of PPAR alpha and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.
DOI	10.1111/bph.14664
收录类别	SCI
语种	英语
WOS记录号	WOS:000470913600004
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/67430
专题	植物化学与西部植物资源持续利用国家重点实验室
通讯作者	Li, Fei
作者单位	1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Yunnan, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Kunming Med Univ, Affiliated Hosp 2, Dept Pathol, Kunming, Yunnan, Peoples R China 4.NCI, Ctr Canc Res, Lab Metab, NIH, Bethesda, MD 20892 USA 5.Jiangxi Univ Tradit Chinese Med, Nanchang, Jiangxi, Peoples R China
推荐引用方式 GB/T 7714	Zhao, Qi,Zhang, Ting,Xiao, Xue-Rong,et al. Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity[J]. BRITISH JOURNAL OF PHARMACOLOGY,2019,176(13):2162-2178.
APA	Zhao, Qi.,Zhang, Ting.,Xiao, Xue-Rong.,Huang, Jian-Feng.,Wang, Yan.,...&Li, Fei.(2019).Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity.BRITISH JOURNAL OF PHARMACOLOGY,176(13),2162-2178.
MLA	Zhao, Qi,et al."Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity".BRITISH JOURNAL OF PHARMACOLOGY 176.13(2019):2162-2178.

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