Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity
Zhao, Qi1,2; Zhang, Ting1,2; Xiao, Xue-Rong1; Huang, Jian-Feng1,2; Wang, Yan3; Gonzalez, Frank J.4; Li, Fei1,5
Corresponding AuthorLi, Fei(
AbstractBackground 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.
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WOS IDWOS:000470913600004
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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.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
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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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