Homocysteine increases HMGreductase: a role in cancer proliferation ?
Effect of lipid-lowering and anti-hypertensive drugs on plasma homocysteine levels. 2007
Elevated plasma concentrations of homocysteine, a sulfur-containing amino acid, are a risk factor for coronary, cerebral and peripheral artery disease. Next to other factors, drugs used for the prevention or treatment of cardiovascular disease may modulate plasma homocysteine levels. Thus, a drug induced homocysteine increase may counteract the desired cardioprotective effect. The aim is to summarize the current knowledge on the effect of two important classes of drugs, lipid-lowering drugs and anti-hypertensive drugs, on homocysteine metabolism. Among the lipid-lowering drugs, especially the fibric acid derivatives, which are used for treatment of hypertriglyceridemia and low HDL-cholesterol, are associated with an increase of homocysteine by 20%-50%. This increase can be reduced, but not totally avoided by the addition of folic acid, vitamin B12 and B6 to fibrates. HMG-CoA reductase inhibitors (statins) do not influence homocysteine concentrations substantially. The effects of nicotinic acid and n3-fatty acids on the homocysteine concentrations are less clear, more studies are necessary to clarify their influence on homocysteine. Antihypertensive drugs have also been studied with respect to homocysteine metabolism. A homocysteine increase has been shown after treatment with hydrochlorothiazide, a lowering was observed after treatment with beta-blockers, but no effect with ACE-inhibitors. The clinical significance of the homocysteine elevation by fibrates and thiazides is not clear. However, individual patients use these drugs for long time, indicating that even moderate increases may be important.
HMG-CoA reductase homocysteine su PubMed 09/2007
Omocisteina legata alla cognizione nel bipolare
Elevati livelli di omocisteina potrebbero avere un impatto negativo su determinate aree della cognizione nei pazienti bipolari eutimici. Questa correlazione è importante a livello clinico in quanto la diminuzione dei livelli di omocisteina è stata associata ad effetti positivi in diverse aree cognitive nei soggetti anziani sani. Sono pertanto necessari con urgenza ulteriori studi che prevedano interventi con acido folico, vitamina B6 e vitamina B12 onde esplorare ulteriormente la correlazione fra livelli di omocisteina e funzionalità cognitiva nel disordine bipolare. Al momento, il livello di omocisteina è stato significativamente ed indipendentemente associato ai punteggi ottenuti nelle aree relative ad apprendimento verbale, memoria ritardata e funzionalità esecutiva. (J Clin Psychiatry 2008; 69: 899-906)
Clin Chem Lab Med. 2005;43(12):1373-6.
Atorvastatin suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells.
Schroecksnadel K, Frick B, Winkler C, Wirleitner B, Weiss G, Fuchs D.
Division of Biological Chemistry, Biocenter, Innsbruck Medical University, and Ludwig Boltzmann Institute of AIDS Research, Innsbruck, Austria.
Hyperhomocysteinemia is regarded as an independent risk factor for vascular diseases, and homocysteine is supposed to contribute to oxidative stress and endothelial damage. Statin therapy is an established intervention to reduce the risk of acute events in patients suffering from cardiovascular diseases. Apart from their lipid-lowering capacity, statins also exert anti-inflammatory and antioxidant effects. As cellular immune activation and oxidative stress play a major role in the pathogenesis of cardiovascular diseases, the anti-inflammatory capacity of statins could partly be responsible for the beneficial effects observed in patients. Earlier we reported that stimulated peripheral blood mononuclear cells (PBMCs) release homocysteine. Here we studied the influence of atorvastatin on homocysteine production in stimulated PBMCs and compared changes in cysteine concentrations and in neopterin production, which is a sensitive indicator of cellular immune activation. Stimulation of human PBMCs with the mitogens concanavalin A and phytohemagglutinin induced significant homocysteine and neopterin production compared to unstimulated cells, whereas cysteine concentrations remained unchanged. Treatment of PBMCs with increasing doses of atorvastatin (10-100 microM) suppressed both biochemical pathways in a dose-dependent manner, and cell proliferation was inhibited in parallel. Again, cysteine levels were not influenced by any treatment. The down-regulating effect of atorvastatin on homocysteine formation in vitro indicates that statins may prevent homocysteine accumulation in the blood via immunosuppression.
Cystathionine beta-synthase is a heme-enzyme
Mild neonatal hypoxia exacerbates the effects of vitamin-deficient diet on homocysteine metabolism in rats.2005
Whereas mRNA levels of cystathionine beta-synthase remained unaltered, folate deficiency reduced the enzyme activity (48.7 +/- 2.9 versus 83.6 +/- 6.3 nmol/h/mg, p < 0.01), an effect potentiated by hypoxia (29.4 +/- 4.7 nmol/h/mg, p < 0.05).
Calpain activation is required for homocysteine-mediated hepatic degradation of inhibitor I kappa B alpha. 2009
J Am Chem Soc. 2009 Sep 9;131(35):12809-16.
Heme regulation of human cystathionine beta-synthase activity: insights from fluorescence and Raman spectroscopy.
Weeks CL, Singh S, Madzelan P, Banerjee R, Spiro TG.
Department of Chemistry, University of Washington, Seattle, Washington 98195, USA.
Cystathionine beta-synthase (CBS) plays a central role in homocysteine metabolism, and malfunction of the enzyme leads to homocystinuria, a devastating metabolic disease. CBS contains a pyridoxal 5'-phosphate (PLP) cofactor which catalyzes the synthesis of cystathionine from homocysteine and serine. Mammalian forms of the enzyme also contain a heme group, which is not involved in catalysis. It may, however, play a regulatory role, since the enzyme is inhibited when CO or NO are bound to the heme. We have investigated the mechanism of this inhibition using fluorescence and resonance Raman spectroscopies. CO binding is found to induce a tautomeric shift of the PLP from the ketoenamine to the enolimine form. The ketoenamine is key to PLP reactivity because its imine C horizontal lineN bond is protonated, facilitating attack by the nucleophilic substrate, serine. The same tautomer shift is also induced by heat inactivation of Fe(II)CBS, or by an Arg266Met replacement in Fe(II)CBS, which likewise inactivates the enzyme; in both cases the endogenous Cys52 ligand to the heme is replaced by another, unidentified ligand. CO binding also displaces Cys52 from the heme. We propose that the tautomer shift results from loss of a stabilizing H-bond from Asn149 to the PLP ring O3' atom, which is negatively charged in the ketoenamine tautomer. This loss would be induced by displacement of the PLP as a result of breaking the salt bridge between Cys52 and Arg266, which resides on a short helix that is also anchored to the PLP via H-bonds to its phosphate group. The salt bridge would be broken when Cys52 is displaced from the heme. Cys52 protonation is inferred to be the rate-limiting step in breaking the salt bridge, since the rate of the tautomer shift, following CO binding, increases with decreasing pH. In addition, elevation of the concentration of phosphate buffer was found to diminish the rate and extent of the tautomer shift, suggesting a ketoenamine-stabilizing phosphate binding site, possibly at the protonated imine bond of the PLP. Implications of these findings for CBS regulation are discussed.
Thromb Haemost. 2005 Feb;93(2):346-50.
Antibodies to N-homocysteinylated albumin as a marker for early-onset coronary artery disease in men.
Undas A, Jankowski M, Twardowska M, Padjas A, Jakubowski H, Szczeklik A.
Department of Medicine, Jagiellonian University School of Medicine, 8 Skawinska Street, 31-066 Cracow, Poland.
N-homocysteinylated (Nepsilon-Hcy) proteins and corresponding antibodies have recently been discovered in humans and animals. Increased autoimmune response to Nepsilon-Hcy-proteins has been reported in stroke patients. The aim of the present study was to investigate whether antibodies against N-homocysteinylated albumin are associated with coronary artery disease (CAD). We studied 88 male patients aged 50 years or under with angiographically documented CAD and 100 age-matched apparently healthy men as controls. Serum levels of IgG antibodies against Nepsilon-Hcy-albumin were determined using an enzymelinked immunosorbent assay. Seropositivity to anti-Nepsilon-Hcy-albumin antibodies was 5-fold more frequent in CAD patients than in controls (52.3% vs 10.0%; p<0.0001). Plasma Hcy levels in CAD patients were also significantly higher in the former than in the latter group (medians, 13.0 microM vs 12.1 microM; p=0.026). Importantly, 41.2% of subjects with plasma total Hcy >14.5 mM were seropositive compared with 25.5% of normohomocysteinemic individuals (p=0.048). There was a weak correlation between anti-Nepsilon-Hcy-albumin antibodies and Hcy levels (r=0.16; p=0.03). By multivariate logistic regression analysis, seropositivity to anti-Nepsilon-Hcy-albumin antibodies was an independent predictor of early CAD (OR, 14.82; 95% CI, 4.47 to 49.19; p=0.00002). Interestingly, anti-Nepsilon-Hcy-albumin antibodies were associated with C-reactive protein levels (r=0.24; p=0.002). Seropositivity to anti-Nepsilon-Hcy-albumin antibodies showed no association with the MTHFR C677T polymorphism. Our results suggest that seropositivity to antibodies against Nepsilon-homocysteinylated albumin is associated with early-onset CAD. An autoimmune response to Nepsilon-Hcy-albumin may represent a novel mechanism involved in the early development of CAD.
J Biol Chem. 2005 Jul 8;280(27):25506-11. Epub 2005 May 17.
Tissue-specific changes in H19 methylation and expression in mice with hyperhomocysteinemia.
Devlin AM, Bottiglieri T, Domann FE, Lentz SR.
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Expression of the imprinted genes H19 and insulin-like growth factor 2 (Igf2), which lie in close proximity on mouse chromosome 7, is regulated by methylation of a differentially methylated domain (DMD) located 5' to H19. Biallelic expression of H19 has been observed in renal disease patients with hyperhomocysteinemia, a cardiovascular disease risk factor. The present study determined whether hyperhomocysteinemia produces decreased tissue methylation capacity, hypomethylation of the H19 DMD, and altered expression of H19 and Igf2 in adult mice. Mice heterozygous for disruption of the gene for cystathionine-beta-synthase (Cbs+/-) and C57BL/6 (Cbs+/+) mice were fed a hyperhomocysteinemic or control diet, respectively, from weaning until 9-12 months of age. Higher plasma total homocysteine (p < 0.001) was found in hyperhomocysteinemic mice than in control mice (95 +/- 12 versus 5.0 +/- 0.3 micromol/liter). Hyperhomocysteinemia was accompanied by higher levels of S-adenosylhomocysteine (p < 0.05) and lower S-adenosylmethionine/S-adenosylhomocysteine ratios (p < 0.001) in liver and brain. The effect of hyperhomocysteinemia on H19 DMD methylation was tissue-specific. In liver, hyperhomocysteinemic mice had decreased H19 DMD methylation (p < 0.001). In brain, hyperhomocysteinemia was accompanied by increased H19 DMD methylation (p < 0.001) and a decrease in the ratio of H19/Igf2 transcripts (p < 0.05). In aorta, hyperhomocysteinemia produced an increase in H19 DMD methylation (p < 0.001) and a 2.5-fold increase in expression of H19 transcripts (p < 0.05). Levels of H19 transcripts in aorta correlated positively with plasma total homocysteine concentration (p < 0.05, r = 0.620). We conclude that hyperhomocysteinemia produces tissue-specific changes in H19 DMD methylation and increased vascular expression of H19 in adult mice.
Devlin AM, Bottiglieri T, Domann FE, Lentz SR.
Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
Expression of the imprinted genes H19 and insulin-like growth factor 2 (Igf2), which lie in close proximity on mouse chromosome 7, is regulated by methylation of a differentially methylated domain (DMD) located 5' to H19. Biallelic expression of H19 has been observed in renal disease patients with hyperhomocysteinemia, a cardiovascular disease risk factor. The present study determined whether hyperhomocysteinemia produces decreased tissue methylation capacity, hypomethylation of the H19 DMD, and altered expression of H19 and Igf2 in adult mice. Mice heterozygous for disruption of the gene for cystathionine-beta-synthase (Cbs+/-) and C57BL/6 (Cbs+/+) mice were fed a hyperhomocysteinemic or control diet, respectively, from weaning until 9-12 months of age. Higher plasma total homocysteine (p < 0.001) was found in hyperhomocysteinemic mice than in control mice (95 +/- 12 versus 5.0 +/- 0.3 micromol/liter). Hyperhomocysteinemia was accompanied by higher levels of S-adenosylhomocysteine (p < 0.05) and lower S-adenosylmethionine/S-adenosylhomocysteine ratios (p < 0.001) in liver and brain. The effect of hyperhomocysteinemia on H19 DMD methylation was tissue-specific. In liver, hyperhomocysteinemic mice had decreased H19 DMD methylation (p < 0.001). In brain, hyperhomocysteinemia was accompanied by increased H19 DMD methylation (p < 0.001) and a decrease in the ratio of H19/Igf2 transcripts (p < 0.05). In aorta, hyperhomocysteinemia produced an increase in H19 DMD methylation (p < 0.001) and a 2.5-fold increase in expression of H19 transcripts (p < 0.05). Levels of H19 transcripts in aorta correlated positively with plasma total homocysteine concentration (p < 0.05, r = 0.620). We conclude that hyperhomocysteinemia produces tissue-specific changes in H19 DMD methylation and increased vascular expression of H19 in adult mice.
Gastroenterology. 2003 Mar;124(3):708-24.
Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress.
Lluis JM, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC.
Liver Unit, Institut of Malalties Digestives, Hospital Clinic i Provincial, IDIBAPS, Department of Experimental Pathology, IIBB, Consejo Superior Investigaciones Científicas, Barcelona, Spain.
Abstract
BACKGROUND & AIMS: Ethanol impairs the mitochondrial transport of reduced glutathione (GSH), resulting in lower mitochondrial GSH (mGSH) levels. Our purpose was to evaluate the role of acetaldehyde on the regulation of mGSH in HepG2 cells.
METHODS: mGSH levels and transport, mitochondrial membrane microviscosity, and lipid composition were determined in mitochondria isolated from acetaldehyde-treated HepG2 cells.
RESULTS: The major ultrastructural changes of acetaldehyde-treated HepG2 cells included cytoplasmic lipid droplets and appearance of swollen mitochondria. Acetaldehyde depleted the mGSH pool size in a time- and dose-dependent fashion with spared cytosol GSH levels. Kinetics of GSH transport into isolated mitochondria from HepG2 cells showed 2 saturable, adenosine triphosphate-stimulated, high- and low-affinity components. Treatment with acetaldehyde increased the Michaelis constant for the high- and low-affinity components, with a greater impact on the former. These changes were due to increased mitochondrial microviscosity by enhanced cholesterol deposition because preincubation with the fluidizing agent, 2-(2-methoxyethoxy) ethyl 8-(cis-2-n-octylcyclopropyl) octanoate, normalized the initial transport rate of GSH into isolated mitochondria. Isolated mitochondria from rat liver enriched in free cholesterol reproduced the disturbing effects of acetaldehyde on GSH transport. The acetaldehyde-stimulated mitochondrial cholesterol content was preceded by increased levels of endoplasmic reticulum (ER)-responsive gene GADD153 and transcription factor sterol regulatory element-binding protein 1 and mimicked by the ER stress-inducing agents tunicamycin and homocysteine. Finally, the mGSH depletion induced by acetaldehyde sensitized HepG2 cells to tumor necrosis factor (TNF)-alpha-induced apoptosis that was prevented by cyclosporin A, GSH ethyl ester, and lovastatin.
CONCLUSIONS: Acetaldehyde sensitizes HepG2 cells to TNF-alpha by impairing mGSH transport through an ER stress-mediated increase in cholesterol.
