Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks

Biesecker, Greg; Karimi, Susan; Desjardins, John; Meyer, Dennis J.; Abbott, Beth; Bendele, Raymond A.; Richardson, Frank C.

doi:10.1016/s0166-3542(03)00005-6

Cited by 57 publications

(49 citation statements)

References 46 publications

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“…In our study, QPCR showed that the normal values of mtDNA fluctuated widely among different animals, which was comparable with the results observed by Biesecher G et al in 2003 [19] . It is important to design experiments with larger sample size to interpret the results more accurately.…”

Section: Discussionsupporting

confidence: 93%

“…It is important to design experiments with larger sample size to interpret the results more accurately. Compared with skeletal muscle, kidney, and liver, the cardiac muscle has the highest cytochrome b/actin ratio, which is consistent with literatures [17,19] . Mitochondrial dysfunction has been most clearly associated with AZT [17] in both humans [29] and in primates [17] , which is consistent with our results in this study.…”

Section: Discussionsupporting

confidence: 92%

“…These specimens were used for extracting mitochondria and determining the activities of respiratory chain complexes and the mitochondrial DNA (mtDNA) contents. Also, some tissues were fixed in 3% glutaraldehyde and were used for the observation of mitochondrial morphology and structure under electron microscope [17,19,20] . Observation of the ultramicro-structure of mitochondria with transmission electron microscope (TEM): Fresh tissues (including liver, kidney, skeletal muscle, and cardiac muscle) were cut into 1 mm cubes, which were fixed in 3% glutaraldehyde for 2 h, and then fixed in 1% osmium tetroxide, stepwise dehydrated in graded acetone, and infiltrated, embedded, and polymerized in EPON 812.…”

Section: Laboratory Studymentioning

confidence: 99%

“…Determination of the activities of respiratory chain complexes I-IV: We used animal tissue mitochondria isolation 1668 www.nature.com/aps Zeng W et al Acta Pharmacologica Sinica npg kit to isolate mitochondria, and used mitochondrial respiratory chain complex determination kit to evaluate the enzyme activities of complexes I (NADH-CoQ reductase), II (sccinateCoQ reductase), III (CoQ-cytochrome C reductase), and IV (cytochrome C oxidase) [17,19] . Also, we used animal mitochondrial protein content determination kit to determine the mitochondrial protein content in animal tissues.…”

Section: Laboratory Studymentioning

confidence: 99%

“…According to the related literature [19] , the following primer sequences were designed and synthesized by Takara Biotechnology (Dalian) Co Ltd.…”

Section: Laboratory Studymentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Section: Laboratory Studymentioning

confidence: 99%

Section: Laboratory Studymentioning

confidence: 99%

“…According to the related literature [19] , the following primer sequences were designed and synthesized by Takara Biotechnology (Dalian) Co Ltd.…”

Section: Laboratory Studymentioning

confidence: 99%

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

et al. 2009

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Discovery and Development of Tenofovir Disoproxil Fumarate

Clercq¹

2011

Antiviral Drugs

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Tenofovir and Adefovir as Antiviral Agents

Cihlář

Delaney

Mackman

2008

Modified Nucleosides

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Over the past decade, nucleotide analogues have emerged as a novel class of clinically effective antiviral agents. Cidofovir was the first antiviral nucleotide to reach commercial approval for the treatment of cytomegalovirus retinitis in 1996. Subsequently, prodrugs of two closely related adenine nucleotide analogues -tenofovir and adefovir -have been licensed for the treatment of human immunodeficiency virus (HIV) and chronic hepatitis B virus (HBV) infections, respectively. Both tenofovir [(R)-9-(2-phosphonomethoxypropyl)adenine; PMPA] and adefovir [9-(2-phosphonomethoxyethyl)adenine; PMEA] ( Figure 24.1) are acyclic nucleoside phosphonates (ANPs), a structurally unique class of nucleotide analogues containing aliphatic sugar-like moieties, covalently attached to phosphonate groups.The concept of ANPs emerged during the mid-1980s [1] as a result of combining the early pursuits of bioisosteric nucleoside phosphonates [2, 3] with clinically validated antiviral acyclic nucleoside analogues such as acyclovir or ganciclovir. In contrast to antiviral nucleosides that require phosphorylation to their corresponding triphosphates in order to become active, two phosphorylation steps are sufficient for the metabolic activation of ANPs. Unlike the phosphate in natural nucleotides and phosphorylated nucleoside analogues (ÀCH 2 ÀOÀP linkage), the bioisosteric phosphonate moiety present in ANPs (ÀOÀCH 2 ÀP linkage) is resistant to enzymatic hydrolysis by phosphatases. Consequently, the active metabolites of ANPs (i.e., ANP diphosphates), which act through potent inhibition of viral polymerases, exhibit prolonged intracellular half-lives [4] and provide persistent antiviral effects [5]. The aliphatic linker mimicking the sugar part of nucleotides possesses multiple rotatable bonds, and offers a greater degree of flexibility to allow ANPs to maintain their potency against genetically diverse viral strains, including a range of drug-resistant viruses.Contrary to the vast majority of therapeutics, ANPs are quite hydrophilic due to two negative charges on their phosphonate moiety present at physiological pH. Although

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Evaluation of mitochondrial DNA content and enzyme levels in tenofovir DF-treated rats, rhesus monkeys and woodchucks

Cited by 57 publications

References 46 publications

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

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

Discovery and Development of Tenofovir Disoproxil Fumarate

Tenofovir and Adefovir as Antiviral Agents

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