A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice

doi:10.1080/00498254.2018.1489167

	A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice
	Wang, Yi-Kun 1,2; Yang, Xiao-Nan 1; Liang, Wei-Qing 3; Xiao, Yao 1,2; Zhao, Qi1,2 ; Xiao, Xue-Rong 1; Gonzalez, Frank J.4; Li, Fei 1
通讯作者	Li, Fei(lifeib@mail.kib.ac.cn)
	2019-06-03
发表期刊	XENOBIOTICA
ISSN	0049-8254
卷号	49 期号:6 页码:655-670
摘要	To elucidate the metabolism of pazopanib, a metabolomics approach was performed based on ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry. A total of 22 pazopanib metabolites were identified in vitro and in vivo. Among these metabolites, 17 were novel, including several cysteine adducts and aldehyde derivatives. By screening using recombinant CYPs, CYP3A4 and CYP1A2 were found to be the main forms involved in the pazopanib hydroxylation. Formation of a cysteine conjugate (M3), an aldehyde derivative (M15) and two N-oxide metabolites (M18 and M20) from pazopanib could induce the oxidative stress that may be responsible in part for pazopanib-induced hepatotoxicity. Morphological observation of the liver suggested that pazopanib (300 mg/kg) could cause liver injury. The aspartate transaminase and alanine aminotransferase in serum significantly increased after pazopanib (150, 300 mg/kg) treatment; this liver injury could be partially reversed by the broad-spectrum CYP inhibitor 1-aminobenzotriazole (ABT). Metabolomics analysis revealed that pazopanib could significantly change the levels of L-carnitine, proline and lysophosphatidylcholine 18:1 in liver. Additionally, drug metabolism-related gene expression analysis revealed that hepatic Cyp2d22 and Abcb1a (P-gp) mRNAs were significantly lowered by pazopanib treatment. In conclusion, this study provides a global view of pazopanib metabolism and clues to its influence on hepatic function.
关键词	Pazopanib hepatotoxicity metabolomics oxidative stress ultra-performance liquid chromatography-electrospray ion source-quadrupole time-of-flight mass spectrometer (UPLC-ESI-QTOFMS)
DOI	10.1080/00498254.2018.1489167
收录类别	SCI
语种	英语
WOS记录号	WOS:000463096200004
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/67714
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.Zhejiang Acad Tradit Chinese Med, Ctr Med Resources Res, Hangzhou, Zhejiang, Peoples R China 4.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
推荐引用方式 GB/T 7714	Wang, Yi-Kun,Yang, Xiao-Nan,Liang, Wei-Qing,et al. A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice[J]. XENOBIOTICA,2019,49(6):655-670.
APA	Wang, Yi-Kun.,Yang, Xiao-Nan.,Liang, Wei-Qing.,Xiao, Yao.,Zhao, Qi.,...&Li, Fei.(2019).A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice.XENOBIOTICA,49(6),655-670.
MLA	Wang, Yi-Kun,et al."A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice".XENOBIOTICA 49.6(2019):655-670.

条目包含的文件		下载所有文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
Wang-2019-A metabolo（1101KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	浏览下载