Qi Zhao1,2, Ting Zhang1,2, Xue-Rong Xiao1, Jian-Feng Huang1,2, Yan Wang3, Frank J Gonzalez4, Fei Li1,5. 1. State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China. 2. University of Chinese Academy of Sciences, Beijing, China. 3. Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China. 4. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. 5. Jiangxi University of Traditional Chinese Medicine, Nanchang, China.
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·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 β-oxidation (β-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 β-FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.
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·kg-1 sunitinib to evaluate sunitinibhepatotoxicity. 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 β-oxidation (β-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 β-FAO and bile acid homeostasis. Activation of PPARα and inhibition of xenobiotic metabolism may be of value in attenuating sunitinibhepatotoxicity.
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