Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice.

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 copy number were all decreased in livers of sunitinib-treated mice, indicating impaired mitochondrial proliferation. Caspase 3 activation and TUNEL-positive hepatocytes were increased in livers of sunitinib-treated mice, indicating hepatocyte apoptosis. In conclusion, sunitinib caused concentration-dependent toxicity in isolated mitochondria at concentrations reached in livers in vivo and inhibited hepatic mitochondrial proliferation. Daily mitochondrial insults and impaired mitochondrial proliferation most likely explain hepatocellular injury observed in mice treated with sunitinib.

• Authors: Franziska Paech, Vanessa F Abegg, Urs Duthaler, Luigi Terracciano, Jamal Bouitbir, Stephan Krähenbühl
• Journal: Toxicology (Toxicology) Vol. 409 Pg. 13-23 (11 01 2018) ISSN: 1879-3185 [Electronic] Ireland
• PMID: 30031043 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• Electron Transport Chain Complex Proteins
• Protein Kinase Inhibitors
• Sunitinib

Topics

• Animals
• Antineoplastic Agents (toxicity)
• Apoptosis (drug effects)
• Electron Transport Chain Complex Proteins (genetics, metabolism)
• Hepatocytes (drug effects, physiology)
• Liver (drug effects, pathology, physiology)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Inbred C57BL
• Mitochondria, Liver (drug effects, physiology)
• Necrosis (chemically induced)
• Protein Kinase Inhibitors (toxicity)
• Sunitinib (toxicity)