Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity.

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 ?-oxidation (?-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 ?-FAO and bile acid homeostasis. Activation of PPAR? and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.

SUBMITTER: Zhao Q 

PROVIDER: S-EPMC6555861 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature