A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice
Wang, Yi-Kun1,2; Yang, Xiao-Nan1; Liang, Wei-Qing3; Xiao, Yao1,2; Zhao, Qi1,2; Xiao, Xue-Rong1; Gonzalez, Frank J.4; Li, Fei1
Corresponding AuthorLi, Fei(lifeib@mail.kib.ac.cn)
Source PublicationXENOBIOTICA
AbstractTo 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.
KeywordPazopanib hepatotoxicity metabolomics oxidative stress ultra-performance liquid chromatography-electrospray ion source-quadrupole time-of-flight mass spectrometer (UPLC-ESI-QTOFMS)
Indexed BySCI
WOS IDWOS:000463096200004
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Document Type期刊论文
Corresponding AuthorLi, Fei
Affiliation1.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
Recommended Citation
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.
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