Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity

  • Br J Pharmacol. 2019 Jul;176(13):2162-2178. doi: 10.1111/bph.14664.
Qi Zhao  1  2 ,  Ting Zhang  1  2 ,  Xue-Rong Xiao  1 ,  Jian-Feng Huang  1  2 ,  Yan Wang  3 ,  Frank J Gonzalez  4 ,  Fei Li  1  5
Affiliations
  • 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.
PMID: 30875096 DOI: 10.1111/bph.14664
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.

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