Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

作者：Qi Zhao, Ting Zhang, Xue‐Rong Xiao, Jian‐Feng Huang, Yan Wang, Frank J. Gonzalez, Fei Li · 发表于：British Journal of Pharmacology · 年份：2019 · DOI：10.1111/bph.14664 · 被引用次数：62 · 研究领域：Liver Disease Diagnosis and Treatment、Drug-Induced Hepatotoxicity and Protection、Histone Deacetylase Inhibitors Research

BACKGROUND AND PURPOSE: Sunitinib is a small-molecule TK inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear. EXPERIMENTAL APPROACH: 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.