| 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
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| Corresponding Author | Li, Fei(lifeib@mail.kib.ac.cn) |
| 2019-07-01 | |
| Source Publication | BRITISH JOURNAL OF PHARMACOLOGY
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| ISSN | 0007-1188 |
| Volume | 176Issue:13Pages:2162-2178 |
| Abstract | 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 |
| Indexed By | SCI |
| Language | 英语 |
| WOS ID | WOS:000470913600004 |
| Citation statistics | |
| Document Type | 期刊论文 |
| Identifier | http://ir.kib.ac.cn/handle/151853/67430 |
| Collection | 植物化学与西部植物资源持续利用国家重点实验室 |
| Corresponding Author | Li, Fei |
| Affiliation | 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 |
| Recommended Citation 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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| zhao2019 (1).pdf（3915KB） | 期刊论文 | 出版稿 | 开放获取 | CC BY-NC-SA | View Download | |
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