Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice

Toxicology
Franziska PaechStephan Krähenbühl

Abstract

Reports concerning hepatic mitochondrial toxicity of sunitinib are conflicting. We therefore decided to conduct a toxicological study in mice. After having determined the highest dose that did not affect nutrient ingestion and body weight, we treated mice orally with sunitinib (7.5 mg/kg/day) for 2 weeks. At the end of treatment, peak sunitinib plasma concentrations were comparable to those achieved in humans and liver concentrations were approximately 25-fold higher than in plasma. Sunitinib did not affect body weight, but increased plasma ALT activity 6-fold. The activity of enzyme complexes of the electron transport chain (ETC) was decreased numerically in freshly isolated and complex III activity significantly in previously frozen liver mitochondria. In previously frozen mitochondria, sunitinib decreased NADH oxidase activity concentration-dependently in both treatment groups. The hepatic mitochondrial reactive oxygen species (ROS) content and superoxide dismutase 2 expression were increased in sunitinib-treated mice. Protein and mRNA expression of several subunits of mitochondrial enzyme complexes were decreased in mitochondria from sunitinib-treated mice. Protein expression of PGC-1α, citrate synthase activity and mtDNA c...Continue Reading

Citations

Oct 13, 2019·Acta Physiologica·Miljenko Valentin PanajatovicJamal Bouitbir
Feb 14, 2020·Expert Opinion on Drug Metabolism & Toxicology·Qiang ShiWilliam B Mattes
Mar 21, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·James C FuscoeQiang Shi

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