Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks.
The antiviral compound tenofovir DF (Gilead Sciences) was evaluated for possible mitochondrial toxicity in rats, rhesus monkeys and woodchucks. Animals were treated by oral gavage with tenofovir DF, and the levels of mitochondrial enzymes cytochrome c oxidase and citrate synthase were assayed. In rats (6/group) treated daily for 28 days with 300 mg/kg tenofovir DF the enzyme levels were unchanged versus control in liver, kidney, and skeletal muscle. In a parallel study, rats (6/group) were treated with 40 mg/kg of the antiviral adefovir dipivoxil (Gilead Sciences) and enzyme levels were also unchanged versus control. In rhesus monkeys (6/group) treated daily with 30 mg/kg or 250 mg/kg tenofovir DF for 56 days, and in woodchucks (6/group) treated daily with 15 mg/kg or 50mg/kg tenofovir DF for 90 days, the enzyme levels were unchanged in liver, kidney, skeletal muscle and cardiac muscle. Mitochondrial DNA (mtDNA) content was determined in tissue from treated versus control animals by utilizing a quantitative real-time PCR (QPCR) technique, where the relative ratios of mitochondrial cytochrome b gene to the genomic actin gene were measured. The relative mtDNA content from rats, rhesus monkeys and woodchucks were unchanged in the various treatment groups. Variations in mtDNA content between animals in the same treatment group were noted. The actual species-dependent mitochondria/genomic ratios were estimated from the QPCR assay. In summary, treatment with tenofovir DF, or with adefovir dipivoxil, did not affect mtDNA content or level of mitochondrial enzymes, and no liver, muscle or renal microscopic abnormalities were observed in tenofovir-treated animals.
Biesecker
Greg
G
OSI Phamaceuticals, 2860 Wilderness Place, Boulder, CO 80301, USA. gbiesecker@osip.com
Karimi
Susan
S
Desjardins
John
J
Meyer
Dennis
D
Abbott
Beth
B
Bendele
Ray
R
Richardson
Frank
F
D000225:Adenine / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000187:drug effects / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000032:analysis / Q000187:drug effects* / Q000235:genetics; D003576:Electron Transport Complex IV / Q000187:drug effects / Q000378:metabolism; D008253:Macaca mulatta; D008392:Marmota; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009928:Organ Specificity; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D013045:Species Specificity; D000068698:Tenofovir
D004272:DNA, Mitochondrial; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase; D000225:Adenine; C106812:adefovir dipivoxil