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Br J Pharmacol. 2019 Mar 15. doi: 10.1111/bph.14664. [Epub ahead of print]

Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity.

Author information

1
State Key Laboratory of Phytochemistry and Plant Resources in West China Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
2
University of Chinese Academy of Sciences, Beijing, China.
3
Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650101, China.
4
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
5
Jiangxi University of Traditional Chinese Medicine, Nanchang, 330004, China.

Abstract

BACKGROUND AND PURPOSE:

Sunitinib is a small molecule tyrosine kinase inhibitor associated with hepatotoxicity. The mechanisms of its toxicity are still unclear.

EXPERIMENTAL APPROACH:

In the present study, mice were treated with 60 mg kg-1, 150 mg kg-1, and 450 mg kg-1 sunitinib to evaluate sunitinib hepatotoxicity. Sunitinib metabolites and endogenous metabolites in liver, serum, feces, and urine were analyzed using ultra-performance liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-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 peroxisome proliferator-activated receptor alpha (PPARα) and inhibition of xenobiotic metabolism may be of value in attenuating sunitinib hepatotoxicity.

KEYWORDS:

Sunitinib; acylcarnitine; bile acid; hepatotoxicity; metabolomics

PMID:
30875096
DOI:
10.1111/bph.14664

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