Mitochondrial sensitivity to AZT

Pereira, Luiz Fernando; Oliveira, Maria Benigna Martinelli de; Carnieri, Eva Gunilla Skare

doi:10.1002/(sici)1099-0844(199809)16:3<173::aid-cbf783>3.0.co;2-4

Cited by 29 publications

(9 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies have shown a direct effect on complex I by NRTIs, for example we have demonstrated an apparent decoupling of complex I with AZT in vitro , and others have suggested an alteration of electron flow through complex I (Pereira et al, 1998;Valenti et al, 2002) as well as alterations in NADH linked respiration with AZT and ddC (Modica-Napolitano, 1993;Skuta et al, 1999;Szabados et al, 1999). Although complex I does have a nucleotide binding site (NADH), there is no evidence to suggest AZT or other NRTIs interfere with NADH binding.…”

Section: Introductionmentioning

confidence: 61%

“…Mitochondrially localized protein kinases such as PKAwhich regulate complex I activity -may provide a mechanistic link between NRTI related disruptions in complex I activity/respiration and evidence of endogenous kinase inhibition by NRTIs. NRTIs (AZT in particular) have been shown to inhibit various nucleotide kinases (Munch-Petersen et al, 1991;McKee et al, 2004;Rylova et al, 2005) as well as metabolic and regulatory kinases (Barile et al, 1994;Pereira et al, 1998;Carnicelli et al, 2006). However, to date, no studies involving PKA and NRTIs have been published.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors

Lund

Wallace

2008

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

Nucleoside analog reverse transcriptase inhibitors (NRTIs) are known to directly inhibit mitochondrial complex I activity as well as various mitochondrial kinases. Recent observations that complex I activity and superoxide production are modulated through cAMP-dependent phosphorylation suggests a mechanism through which NRTIs may affect mitochondrial respiration via kinase-dependent protein phosphorylation. In the current study, we examine the potential for NRTIs to inhibit the cAMP-dependent phosphorylation of complex I and the associated NADH:CoQ oxidoreductase activities and rates of superoxide production using HepG2 cells. Phosphoprotein staining of immunocaptured complex I revealed that 3'-azido-3'-deoxythymidine (AZT; 10 and 50 microM), AZT monophosphate (150 microM), and 2',3'-dideoxycytidine (ddC; 1 microM) prevented the phosphorylation of the NDUFB11 subunit of complex I. This was associated with a decrease in complex I activity with AZT and AZT monophosphate only. In the presence of succinate, superoxide production was increased with 2',3'-dideoxyinosine (ddI; 10 microM) and ddC (1 microM). In the presence of succinate+cAMP, AZT showed an inverse dose-dependent effect on superoxide production. None of the NRTIs examined inhibit PKA activity suggesting that the observed effects are due to a direct interaction with complex I. These data demonstrate a direct effect of NRTIs on cAMP-dependent regulation of mitochondrial bioenergetics independent of DNA polymerase-gamma activity; in the case of AZT, these observations may provide a mechanism for the observed long-term toxicity with this drug.

show abstract

Section: Introductionmentioning

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors

Lund

Wallace

2008

Toxicology and Applied Pharmacology

View full text Add to dashboard Cite

show abstract

“…Carbonyl groups also may be introduced into proteins by glycoxidation and lipid peroxidation products. 20,21 The absence of such a response in CSF obtained from patients with MS suggests that neuroinflammatory responses alone are likely not sufficient to cause mitochondrial dysfunction. 14 Once the proteins are oxidized they are cleaved by proteases 14 and thus would likely have access to the CSF.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants

Turchan¹,

Pocernich²,

Gairola³

et al. 2003

Neurology

175

166

View full text Add to dashboard Cite

show abstract

“…Indicating a severe effect at the level of respiratory complex-I [14], particularly at the sub-complex-I β [15]. The enhanced H 2 O 2 content induces a large increase in reactive oxygen species (ROS) and peroxynitrite production that causes single strand DNA breaks, lipid peroxidation, protein oxidation/nitration, and mitochondrial DNA (mtDNA) oxidation [16, 17].…”

Section: Introductionmentioning

confidence: 99%

A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver

Butanda-Ochoa

Hernández-Espinosa

Olguín-Martínez

et al. 2017

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

The 3′-azido-3′-deoxythymidine or Zidovudine (AZT) was the first antiretroviral drug used in the treatment of HIV patients, which has good effectiveness but also hepatotoxic side effects that include cell cycle arrest and oxidative/nitrative mitochondrial damage. Whether such an oxidative damage may affect the proliferative-regenerative capacity of liver remains to be clearly specified at doses commonly used in the clinical practice. In this study, we described the oxidative-proliferative effect of AZT administered at a common clinical dose in rat liver submitted to 70% partial hepatectomy (PH). The results indicate that AZT significantly decreased DNA synthesis and the number of mitosis in liver subjected to PH in a synchronized way with the promotion of organelle-selective lipid peroxidation events (especially those observed in plasma membrane and cytosolic fractions) and with liver enzyme release to the bloodstream. Then at the dose used in clinical practice AZT decreased liver regeneration but stimulates oxidative events involved during the proliferation process in a way that each membrane system inside the cell preserves its integrity in order to maintain the cell proliferative process. Here, the induction of large amounts of free ammonia in the systemic circulation could become a factor capable of mediating the deleterious effects of AZT on PH-induced rat liver regeneration.

show abstract

Mitochondrial sensitivity to AZT

Cited by 29 publications

References 49 publications

Adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors

Adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent phosphoregulation of mitochondrial complex I is inhibited by nucleoside reverse transcriptase inhibitors

Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants

A Single Zidovudine (AZT) Administration Delays Hepatic Cell Proliferation by Altering Oxidative State in the Regenerating Rat Liver

Contact Info

Product

Resources

About