Long-Term Exposure to AZT, but not d4T, Increases Endothelial Cell Oxidative Stress and Mitochondrial Dysfunction
- 9 December 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cardiovascular Toxicology
- Vol. 9 (1), 1-12
- https://doi.org/10.1007/s12012-008-9029-8
Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (AZT) and stavudine (d4T), cause toxicities to numerous tissues, including the liver and vasculature. While much is known about hepatic NRTI toxicity, the mechanism of toxicity in endothelial cells is incompletely understood. Human aortic endothelial and HepG2 liver cells were exposed to 1 μM AZT or d4T for up to 5 weeks. Markers of oxidative stress, mitochondrial function, NRTI phosphorylation, mitochondrial DNA (mtDNA) levels, and cytotoxicity were monitored over time. In endothelial cells, AZT significantly oxidized glutathione redox potential, increased total cellular and mitochondrial-specific superoxide, decreased mitochondrial membrane potential, increased lactate release, and caused cell death from weeks 3 through 5. Toxicity occurred in the absence of di- and tri-phosphorylated AZT and mtDNA depletion. These data show that oxidative stress and mitochondrial dysfunction in endothelial cells occur with a physiologically relevant concentration of AZT, and require long-term exposure to develop. In contrast, d4T did not induce endothelial oxidative stress, mitochondrial dysfunction, or cytotoxicity despite the presence of d4T-triphosphate. Both drugs depleted mtDNA in HepG2 cells without causing cell death. Endothelial cells are more susceptible to AZT-induced toxicity than HepG2 cells, and AZT caused greater endothelial dysfunction than d4T because of its pro-oxidative effects.Keywords
This publication has 60 references indexed in Scilit:
- Relevance of experimental models for investigation of genotoxicity induced by antiretroviral therapy during human pregnancyMutation research. Reviews in mutation research, 2008
- Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruptionAmerican Journal of Physiology-Heart and Circulatory Physiology, 2007
- Absence of a Universal Mechanism of Mitochondrial Toxicity by Nucleoside AnalogsAntimicrobial Agents and Chemotherapy, 2007
- Simple quantitative detection of mitochondrial superoxide production in live cellsBiochemical and Biophysical Research Communications, 2007
- Measurement of Reactive Oxygen Species in Cardiovascular StudiesHypertension, 2007
- Zidovudine Inhibits Thymidine Phosphorylation in the Isolated Perfused Rat HeartAntimicrobial Agents and Chemotherapy, 2007
- Selective fluorescent imaging of superoxide in vivo using ethidium-based probesProceedings of the National Academy of Sciences of the United States of America, 2006
- 3′-Azido-3′-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondriaBiochemical Pharmacology, 2006
- Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol γ hypothesisAIDS, 2006
- Effects of 3′-azido-3′-deoxythymidine on the deoxynucleotide triphosphate pools of cultured human cellsBiochemical and Biophysical Research Communications, 1988