Toxicity of thiols and disulphides: Involvement of free-radical species

Munday, Rex

doi:10.1016/0891-5849(89)90147-0

Cited by 286 publications

(185 citation statements)

References 136 publications

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“…Inconsistent with the hypothesis of an increased oxidant stress, a decrease in LDL susceptibility to oxidation and in plasma peroxidation indicators was reported in homozygous patients for CBS deficiency (Blom et al, 1992Dudman et al, 1993;Jones et al, 1994). Although a low concentration of homocysteine in its reduced form behaves as a pro-oxidant, in high concentration, homocysteine, like other thiols, presents a free-radical scavenger activity (Munday, 1989). This bivalent effect of aminothiols (pro-oxidant and antioxidant), confirmed for in vitro LDL oxidation (Halvorsen et al, 1996), might explain the discrepancies observed between moderate and severe hyperhomocysteinemia.…”

Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 91%

“…Although cytotoxicity was not specific to homocysteine, endothelial cell detachment is also observed with cysteine (Dudman et al, 1991), an increase in the hydrogen peroxidesensitive cellular fluorescent probe, 2',7'-dichlorofluorescein, was observed in cultured endothelial cells exposed to homocysteine (Toborek and Hennig, 1996). Besides the initiation of lipid peroxidation at the cell surface, homocysteine auto-oxidation with trace metal ions, generating reactive oxygen species such as superoxide anion, hydrogen peroxide, hydroxyl, and thiol free radicals (Munday, 1989;Schöneich et al, 1989), would directly oxidize low-density lipoprotein (LDL) (Heinecke et al, 1987;Hirano et al, 1994;Wood and Graham, 1995). Homocysteine would also contribute to the LDL oxidative modifications mediated by endothelial cells, macrophages, and smooth muscle cells (Heinecke et al, 1987;Sparrow and Olszewski, 1993;Wood and Graham, 1995), which are deeply involved in the initial steps of atherogenesis.…”

Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 95%

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Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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SUMMARY:Based on recent retrospective, prospective, and experimental studies, mild to moderate elevation of fasting or postmethionine-load plasma homocysteine is accepted as an independent risk factor for cardiovascular disease and thrombosis in both men and women. Hyperhomocysteinemia results from an inhibition of the remethylation pathway or from an inhibition or a saturation of the transsulfuration pathway of homocysteine metabolism. The involvement of a high dietary intake of methionine-rich animal proteins has not yet been investigated and cannot be ruled out. However, folate deficiency, either associated or not associated with the thermolabile mutation of the N 5,10 -methylenetetrahydrofolate reductase, and vitamin B 6 deficiency, perhaps associated with cystathionine ␤-synthase defects or with methionine excess, are believed to be major determinants of the increased risk of cardiovascular disease related to hyperhomocysteinemia. Recent experimental studies have suggested that moderately elevated homocysteine levels are a causal risk factor for atherothrombotic disease because they affect both the vascular wall structure and the blood coagulation system. The oxidant stress that results from impaired homocysteine metabolism, which modifies the intracellular redox status, might play a central role in the molecular mechanisms underlying moderate hyperhomocysteinemia-mediated vascular disorders. Because folate supplementation can efficiently reduce plasma homocysteine levels, both in the fasting state and after methionine loading, results from further prospective cohort studies and from on-going interventional trials will determine whether homocysteine-lowering therapies can contribute to the prevention and reduction of cardiovascular risk. Additionally, these studies will provide unequivocal arguments for the independent and causal relationship between hyperhomocysteinemia and atherothrombotic disease. (Lab Invest 2001, 81:645-672).C ardiovascular diseases remain the leading cause of mortality in Western populations. Hyperlipoproteinemia, hypertension, diabetes, obesity, and tobacco smoking are the main risk factors for atherosclerosis and its thrombotic complications. However, these factors alone cannot account for all of the deaths caused by vascular pathologies.As early as 1969, clinical studies conducted in homocystinuric children revealed the importance of severe hyperhomocysteinemia in premature development of atherosclerosis and thromboembolism (McCully, 1983). According to numerous retrospective case-controlled studies, moderate increases in plasma homocysteine, which can be precisely quantitated by high performance liquid chromatography (HPLC), raise the risk for cardiovascular disease 2-fold, after adjusting for classic risk factors. Moreover, up to 20% to 40% of patients with vascular pathologies present moderate to intermediate hyperhomocysteinemia. However, results from prospective studies are inconsistent. Additionally, molecular mechanisms underlying hyperhomocysteinemia-induced vascular diseas...

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Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 91%

Section: Hyperhomocysteinemia-mediated Oxidant Stress Through Imbalanmentioning

confidence: 95%

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Durand

Prost²,

Loreau

et al. 2001

Laboratory Investigation

232

147

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“…Although cysteine used for GSH synthesis can be obtained from protein breakdown, its availability mainly depends on the cysteine content of the diet [18]. However, cysteine also causes toxicity related to its autoxidation of the corresponding disulfide, which can even decrease GSH levels [19,20]. Some enzymes can convert the oxidized form of cysteine back to its unmodified form, but the presence of cysteine residues in proteins makes them susceptible to oxidative stress and associated damage [21].…”

Section: Introductionmentioning

confidence: 99%

Has removal of excess cysteine led to the evolution of pheomelanin?

2012

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“…[2][3][4][5][6][7][8] These aminothiols have a critical role as intracellular redox buffers, and it is also becoming increasingly recognized that they comprise an important extracellular redox system. 9,10 It has also been reported that homocysteine exerts its detrimental effects in part through a mechanism involving oxidative stress. 11,12 The renin-angiotensin system has an important role in the development of cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Homocysteine-induced oxidative stress upregulates chymase in mouse mastocytoma cells

et al. 2009

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Reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ), O À 2 and OH participate in the pathogenesis of ischemia/ reperfusion injury, inflammation and atherosclerosis. Our previous studies have suggested that increased angiotensin II (Ang II)-forming chymase may be involved in the development of atherosclerosis. However, the regulatory mechanism of chymase expression has not yet been clarified. In this study, we tested whether oxidative stress upregulates mouse mast cell proteinase chymase, mouse mast cell proteinase (MMCP)-5 or MMCP-4. We also examined the expression and activity of these proteins after treatment. Cultured mouse mastocytoma cells (MMC) displaying chymase-dependent Ang II-forming activity were treated with H 2 O 2 and several aminothiols with or without anti-oxidants. The levels of MMCP-5 and MMCP-4 expression were determined by quantitative RT-PCR; the level of chymase-dependent Ang II-forming activity was measured by high performance liquid chromatography using Ang I as a substrate. Treatment of MMC with homocysteine (0.1-3 mmol l -1 ) significantly increased MMCP-5 and MMCP-4 expression, as well as Ang II-forming activity. These effects were significantly inhibited by the addition of catalase and further suppressed by the combination of catalase and superoxide dismutase. Incubation with hydrogen peroxide alone caused a significant increase in Ang II-forming activity, which was completely suppressed by co-treatment with catalase. Furthermore, MMCP-5 and MMCP-4 expression levels were drastically suppressed and chymase induction by homocysteine was diminished under the GATA-inhibited condition. Homocysteine increased mast cell chymase expression and activity through the mechanism of oxidative stress. Our results suggest that there is a biochemical link between oxidative stress and the local Ang IIforming system.

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Toxicity of thiols and disulphides: Involvement of free-radical species

Cited by 286 publications

References 136 publications

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Impaired Homocysteine Metabolism and Atherothrombotic Disease

Has removal of excess cysteine led to the evolution of pheomelanin?

Homocysteine-induced oxidative stress upregulates chymase in mouse mastocytoma cells

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