Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice
| Autor: | Vanessa F. Abegg, Urs Duthaler, Stephan Krähenbühl, Luigi Terracciano, Jamal Bouitbir, Franziska Paech |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Antineoplastic Agents Apoptosis Mitochondria Liver Mitochondrion urologic and male genital diseases Toxicology Superoxide dismutase 03 medical and health sciences Mice Necrosis 0302 clinical medicine Internal medicine medicine Sunitinib Citrate synthase Animals Protein Kinase Inhibitors chemistry.chemical_classification Membrane Potential Mitochondrial Reactive oxygen species biology medicine.disease female genital diseases and pregnancy complications 3. Good health Mice Inbred C57BL Mitochondrial toxicity 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Electron Transport Chain Complex Proteins Liver 030220 oncology & carcinogenesis Hepatocyte biology.protein Hepatocytes medicine.drug |
| Zdroj: | Toxicology. 409 |
| ISSN: | 1879-3185 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect