In vivo assessment of mitochondrial toxicity of metacavir in Rhesus monkeys after three months of intravenous administration

• Published in: Acta pharmacologica Sinica Vol. 30; no. 12; pp. 1666 - 1673
• Main Authors: Zeng, Wen, Cheng, An-chun, Chen, Zheng-li, Luo, Qi-hui, Sun, Yu-bo, Li, Zhan, Bi, Feng-jun
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2009
• Subjects: Animals; DNA, Mitochondrial - metabolism; Electron Transport Complex I - metabolism; Electron Transport Complex II - metabolism; Female; Heart - drug effects; Injections, Intravenous; Kidney - drug effects; Kidney - metabolism; Kidney - ultrastructure; Liver - drug effects; Liver - metabolism; Liver - ultrastructure; Macaca mulatta; Male; Mitochondria - drug effects; Mitochondria - physiology; Mitochondria - ultrastructure; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - ultrastructure; Myocardium - metabolism; Myocardium - ultrastructure; Original; Purine Nucleosides - administration & dosage; Purine Nucleosides - agonists; Zidovudine - pharmacology; 恒河猴; 恢复阶段; 线粒体DNA; 透射电子显微镜; 静脉注射
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2009.163

Aim： To explore the potential mitochondrial toxicities and their severities of intravenously administered metacavir, a nucleoside analog, in rhesus monkeys. Methods： Totally 21 rhesus monkeys were randomly divided into 4 groups： metacavir 120 mg/kg group, metacavir 40 mg/kg group, zidovudine（AZT） 50 mg/kg group, and blank control group. Animals were killed after the completion of dosing or further observed in a 4-week recovery phase. Changes of structure of mitochondria in liver, kidney, skeletal muscles, and cardiac muscles were observed under transmission electron microscope（TEM）. Changes of the activities of mitochondrial respiratory chain complexes and mitochondrial DNA were also determined. Results： In metacavir 120 mg/kg group, some mitochondrial injuries were found in skeletal muscle, cardiac muscle, and liver, including that some cristae was broken and became sparse in density in the skeletal muscle, the morphology and size of mitochondria remained unchanged. Metacavir decreased the activities of respiratory chain complexes Ⅰ and Ⅱ and the mtDNA contents in three tissues in a dose-dependent manner; however, the extent of such decrease was lower than that in AZT 50 mg/kg group. The mitochondrial injuries in metacavir 40 mg/kg group were mild in each tissue and no obvious change in mitochondrial function was noted. On week 4 in the recovery phase, results showed that all these injuries were reversible after drug withdrawal. Conclusion： These results suggest that metacavir has not a high risk for potential mitochondrial-related effects in rhesus monkeys.