3′-Azido-3′-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria

Lynx, Matthew D.; McKee, Edward E.

doi:10.1016/j.bcp.2006.04.004

Cited by 61 publications

(50 citation statements)

References 37 publications

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“…However, other research has shown that AZT is slowly phosphorylated, if at all, beyond AZTMP in many tissues [2,3,5]. Past research from this laboratory has shown that AZT competitively inhibits thymidine kinase 2 in isolated rat heart and liver mitochondria [6] and in the perfused whole rat heart [7]. In the isolated mitochondria, the K i values for inhibition of thymidine phosphorylation are 10.6 ± 4.5 μM AZT for heart mitochondria and 14.0 ± 2.5 μM AZT for liver mitochondria [6].…”

Section: Introductionmentioning

confidence: 94%

“…Past research from this laboratory has shown that AZT competitively inhibits thymidine kinase 2 in isolated rat heart and liver mitochondria [6] and in the perfused whole rat heart [7]. In the isolated mitochondria, the K i values for inhibition of thymidine phosphorylation are 10.6 ± 4.5 μM AZT for heart mitochondria and 14.0 ± 2.5 μM AZT for liver mitochondria [6]. This suggests that AZT inhibits thymidine phosphorylation much more readily than AZTTP inhibits polymerase γ.…”

Section: Introductionmentioning

confidence: 95%

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Effect of AZT on thymidine phosphorylation in cultured H9c2, U-937, and Raji cell lines

Lynx¹,

Kang²,

McKee³

2008

Biochemical Pharmacology

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Abstract3′-azido-3′-deoxythymidine (AZT) has been shown to be a potent inhibitor of thymidine kinase 2 in work from this laboratory. Inhibition results in decreased salvage of thymidine to TTP, which may lead to depletion of the TTP pool and result in the mitochondrial dysfunction and mt-DNA depletion observed with AZT toxicity. The effect of AZT on thymidine phosphorylation in growing cells expressing thymidine kinase 1 has not been shown. Three cell lines were used in these experiments: H9c2, derived from rat cardiomyoblasts; U-937, derived from human monocytes; and Raji, derived from human lymphoblasts. AZT inhibited growth in a concentration dependent manner in U-937 cells, but not the other cell lines. The phosphorylation of [3H]-thymidine or [3H]-AZT was determined during log growth. All cell lines salvaged and phosphorylated thymidine to TTP, with TTP the major product. The U-937 cells had a much more active salvage pathway than the other cells. All cell lines phosphorylated AZT to the triphosphate, but the major product was AZTMP. The AZT inhibition of growth of the U-937 cells did not correlate with levels of phosphorylated AZT. In contrast, pro-drug AZT was shown to inhibit thymidine phosphorylation in all lines with 50% inhibition concentrations (IC50) ranging from 4.4-21.9 μM. Since the U-937 cells expressed higher activity of the salvage pathway than the other cell lines, the U-937 cells may rely more heavily on the salvage pathway for TTP synthesis, accounting for AZT inhibition of growth.

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 95%

Effect of AZT on thymidine phosphorylation in cultured H9c2, U-937, and Raji cell lines

Lynx¹,

Kang²,

McKee³

2008

Biochemical Pharmacology

Self Cite

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“…[28][29][30] Apart from their direct effect on mtDNA polymerase γ, nucleoside analogues may also compete with endogenous nucleosides for phosphorylation by mitochondrial thymidine kinase 2 and also for transport into the mitochondria. 31,32 Evidence is now emerging that NRTIs may increase the rate of accumulation of mtDNA mutations, and increased mutations have been demonstrated longitudinally in peripheral leukocytes in Figure 1: Selected endogenous nucleosides and their corresponding antiviral drug analogues patients on HAART. 33 In addition, Maagaard et al found increased mtDNA deletions in the skeletal muscle of patients exposed to NRTIs, 34 and reduced mitochondrial gene expression has been demonstrated in adipocytes exposed to NRTIs.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction and human immunodeficiency virus infection

Watt

2011

Journal of Endocrinology, Metabolism and Diabetes of South Afri

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Human immunodeficiency virus (HIV) infection and the pharmacological treatment thereof have both been shown to affect mitochondrial function in a number of tissues, and each may cause specific organ pathology through specific mitochondrial pathways. HIV has been shown to kill various tissue cells by activation of mitochondrial apoptosis. Nucleoside analogues, used extensively to treat HIV infection, are known to influence a number of steps affecting mitochondrial DNA integrity. This review describes the basic physiology, pharmacology and pathophysiology of HIV infection and the nucleoside analogues regarding mitochondrial function and discusses the progress made in this field with respect to the measurement of these effects and the prediction of potential drug toxicity.Peer reviewed.

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“…AZT is a well-known anti-HIV drug of nucleoside reverse transcriptase class, used as one of the main drug components of highly active anti-retroviral therapy (HAART). The toxic influences on mitochondria are widely described: AZT depleted mitochondrial DNA in isolated rat liver and heart mitochondria, 15 caused dysfunction of mitochondrial respiratory chain, leading to anaerobic ATP synthesis and lactic acid production, 16 histopathological and ultrastructural changes of mitochondria, 17 and oxidative stress by activation of reactive oxygen species. 18 These events are considered as the main causes leading to severe side effects such as hepatotoxicity, 19 cardiac and skeletal muscle pathologies, peripheral neuropathy, pancreatitis, lactic acidosis, and bone marrow suppression.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

Pupure

Férnandes

Santos

et al. 2008

Cell Biochemistry & Function

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Previously mildronate, an aza-butyrobetaine derivative, was shown to be a cytoprotective drug, through its mechanism of action of inhibition of carnitine palmitoyltransferase-1, thus protecting mitochondria from long-chain fatty acid accumulation and subsequent damage. Recently in an azidothymidine (AZT)-induced cardiotoxicity model in vivo (in mice), we have found mildronate's ability of protecting heart tissue from nuclear factor kB abnormal expression. Preliminary data also demonstrate cerebro-and hepatoprotecting properties of mildronate in AZT-toxicity models. We suggest that mildronate may target its action predominantly to mitochondria. The present study in isolated rat liver mitochondria was designed to clarify mitochondrial targets for mildronate by using AZT as a model compound. The aim of this study was to investigate: (1) whether mildronate may protect mitochondria from AZT-induced toxicity; and (2) which is the most critical target in mitochondrial processes that is responsible for mildronate's regulatory action. The results showed that mildronate protected mitochondria from AZT-induced damage predominantly at the level of complex I, mainly by reducing hydrogen peroxide generation. Significant protection of AZT-caused inhibition of uncoupled respiration, ADP to oxygen ratio, and transmembrane potential were also observed. Mildronate per se had no effect on the bioenergetics, oxidative stress, or permeability transition of rat liver mitochondria. Since mitochondrial complex I is the first enzyme of the respiratory electron transport chain and its damage is considered to be responsible for different mitochondrial diseases, we may account for mildronate's effectiveness in the prevention of pathologies associated with mitochondrial dysfunctions.

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3′-Azido-3′-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria

Cited by 61 publications

References 37 publications

Effect of AZT on thymidine phosphorylation in cultured H9c2, U-937, and Raji cell lines

Effect of AZT on thymidine phosphorylation in cultured H9c2, U-937, and Raji cell lines

Mitochondrial dysfunction and human immunodeficiency virus infection

Mitochondria as the target for mildronate's protective effects in azidothymidine (AZT)‐induced toxicity of isolated rat liver mitochondria

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