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


CONCLUSIONS
These results suggest that metacavir has not a high risk for potential mitochondrial-related effects in rhesus monkeys.
Zeng
Wen
W
Engineering and Technology Center for Laboratory Animals of Sichuan Agricultural University, Ya-an, China. zengwen10@vip.163.com
Cheng
An-chun
AC
Chen
Zheng-li
ZL
Luo
Qi-hui
QH
Sun
Yu-bo
YB
Li
Zhan
Z
Bi
Feng-jun
FJ
D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism*; D042963:Electron Transport Complex II / Q000378:metabolism*; D005260:Female; D006321:Heart / Q000187:drug effects; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008253:Macaca mulatta; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D011684:Purine Nucleosides / Q000008:administration & dosage / Q000819:agonists*; D015215:Zidovudine / Q000494:pharmacology
C529213:2-amino-9-(2,3-dideoxy-2,3-dihydroarabinofuranosyl)-6-methoxy-9H-purine; D004272:DNA, Mitochondrial; D011684:Purine Nucleosides; D015215:Zidovudine; D042963:Electron Transport Complex II; D042967:Electron Transport Complex I