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Mechanisms of Increased Vascular Oxidant Stress in Hyperhomocysteinemia and Its Impact on Endothelial Function

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Elevated plasma levels of homocysteine are associated with an increased generation of reactive oxygen species in aortas of hyperhomocysteinemic animals and in endothelial cells. This may contribute to endothelial dysfunction observed in hyperhomocysteinemia, and promote atherosclerotic vascular disease. Homocysteine seems to promote the formation of reactive oxygen species primarily by a biochemical mechanism involving endothelial nitric oxide synthase, as increased endothelial lipid peroxidation and oxidation of the redox-sensitve dye 2',7'-dichlorofluoresceine could only be observed after incubation of endothelial cells with L-, but not with D-homocysteine, and could be prevented by inhibition of endothelial nitric oxide synthase. An increased oxidation rate of aminothiols in plasma, as observed in patients with hyperhomocysteinemia, further contributes to increased generation of reactive oxygen species. These effects are amplified by a homocysteine-specific inhibition of cellular antioxidant enzymes, like superoxide dismutase and the cellular isoform of gluthatione peroxidase. All mechanisms together result in increased levels of superoxide anion and peroxyl radicals in the vasculature that react with nitric oxide to form peroxnitrites. This abolishes nitric oxide's bioactivity and contributes to endothelial dysfunction. In addition, increased vascular oxidant stress in hyperhomocysteinemia has been shown to activate proinflammatory signaling pathways in endothelial cells, like the transcription factor NF-κB. This leads to increased endothelial expression of chemokines and adhesion molecules that promote the recruitment, adhesion and transmigration of circulating leukocytes to the vessel wall. All these mechamisms may contribute to the increased risk for cardiovascular diseases associated with hyperhomocysteinemia.
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Keywords: atherosclerosis; endothelial dysfunction; gluthatione peroxidase; homocysteine; nf-kb; nitric oxide; oxidant stress; reactive oxygen species

Document Type: Review Article

Affiliations: Medizinische Poliklinik -Innenstadt, Klinikum der Universitat M√ľnchen, Pettenkoferstrasse 8a, D- 80336 Munchen, Germany.

Publication date: February 1, 2005

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  • Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:

    In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.
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