AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins.

Asunción, José García de la; Olmo, María L. del; Sastre, Juan; Millán, A; Pellı́n, Antonio; Pallardó, Federico V.; Viña, José

doi:10.1172/jci1418

Cited by 174 publications

(81 citation statements)

References 34 publications

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“…Lipid hydroperoxide levels in diabetic rats were significantly higher than in control rats. Indeed, the values in tissues from diabetic animals were 190% (heart), 250% (18 -20) and in many age-associated (21) and toxicologic (22) diseases. Thus, we studied the effect of diabetes on peroxide generation by mitochondria in liver, heart, and kidney from control and diabetic rats.…”

Section: Resultsmentioning

confidence: 99%

Xanthine Oxidase Is Involved in Free Radical Production in Type 1 Diabetes

et al. 2002

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The aim of this work was to study the mechanism of free radical formation in type 1 diabetes and its possible prevention. We have found oxidation of blood glutathione and an increase in plasma lipoperoxide levels in both human type 1 diabetes and experimental diabetes. Peroxide production by mitochondria does not increase in diabetes. On the contrary, the activity of xanthine oxidase, a superoxide-generating enzyme, increases in liver and plasma of diabetic animals. The increase in plasma xanthine oxidase activity may be explained by the increase in the hepatic release of this enzyme, which is not due to nonspecific membrane damage: release of other hepatic enzymes, such as the amino transferases, does not increase in diabetes. Superoxide formation by aortic rings of rabbits increases significantly in diabetes. This is completely inhibited by allopurinol, an inhibitor of xanthine oxidase. Heparin, which releases xanthine oxidase from the vessel wall, also decreases superoxide formation by aortic rings of diabetic animals. Treatment with allopurinol decreases oxidative stress in type 1 diabetic patients: hemoglobin glycation, glutathione oxidation, and the increase in lipid peroxidation are prevented. These results may have clinical significance in the prevention of late-onset vascular complications of diabetes.

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Section: Resultsmentioning

confidence: 99%

Xanthine Oxidase Is Involved in Free Radical Production in Type 1 Diabetes

et al. 2002

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“…Oxidative stress and mtDNA depletion have been the suggested mechanisms, particularly in CM. [33][34][35][36][37][38][39][40][41][42][43][44][45][46] They may be critical pathogenetically because reactive oxygen species (ROS) are produced abundantly in mitochondria when electron transport chain (ETC) activity is disrupted. [47][48][49] ROS are also known to damage ETC complexes cyclically leading to increased ROS (induced by AZT), impaired respiration and further increases in ROS production, etc.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

Kohler

Cucoranu

Fields

et al. 2009

Laboratory Investigation

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Transgenic mice (TG) were used to define mitochondrial oxidative stress and cardiomyopathy (CM) induced by zidovudine (AZT), an antiretroviral used to treat HIV/AIDS. Genetically engineered mice either depleted or overexpressed mitochondrial superoxide dismutase (SOD2 þ /À KOs and SOD2-OX, respectively) or expressed mitochondrially targeted catalase (mCAT). TGs and wild-type (WT) littermates were treated (oral AZT, 35 days). Cardiac mitochondrial H 2 O 2 , aconitase activity, histology and ultrastructure were analyzed. Left ventricle (LV) mass and LV end-diastolic dimension were determined echocardiographically. AZT induced cardiac oxidative stress and LV dysfunction in WTs. Cardiac mitochondrial H 2 O 2 increased and aconitase was inactivated in SOD2 þ /À KOs, and cardiac dysfunction was worsened by AZT. Conversely, the cardiac function in SOD2-OX and mCAT hearts was protected. In SOD2-OX and mCAT TG hearts, mitochondrial H 2 O 2 , LV mass and LV cavity volume resembled corresponding values from vehicle-treated WTs. AZT worsens cardiac dysfunction and increases mitochondrial H 2 O 2 in SOD2 þ /À KO. Conversely, both SOD2-OX and mCAT TGs prevent or attenuate AZT-induced cardiac oxidative stress and LV dysfunction. As dysfunctional changes are ameliorated by decreasing and worsened by increasing H 2 O 2 abundance, oxidative stress from H 2 O 2 is crucial pathogenetically in AZT-induced mitochondrial CM.

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“…34 AZT had no effect at the level of complex II on mitochondrial bioenergetics of rat liver and kidney, 34 and heart. 35 AZT also induced an increase in H 2 O 2 production in rat peritoneal macrophages, 36 and in AZT-treated mice muscle mitochondria, 37 as well as inhibition of NADH cytochrome C reductase, an enzyme of complex I. 38,39 Nevertheless, in rat heart mitochondria, different data were obtained: no influence on bioenergetics and Ca 2þ loading capacity at 0.01 mM, while inhibition of glutamate/malatedependent RCR with corresponding increase in the rate of state 4 at 0.1 mM were found.…”

Section: Discussionmentioning

confidence: 96%

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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AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins.

Cited by 174 publications

References 34 publications

Xanthine Oxidase Is Involved in Free Radical Production in Type 1 Diabetes

Xanthine Oxidase Is Involved in Free Radical Production in Type 1 Diabetes

Transgenic mitochondrial superoxide dismutase and mitochondrially targeted catalase prevent antiretroviral-induced oxidative stress and cardiomyopathy

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

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