Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have discussed in this review many features and possible mechanisms responsible for the development of alcoholic cardiomyopathy. The evidence suggests that defects in myofibrillar protein turnover occur in both acute and chronic alcohol studies. Possible mechanisms to explain poor contractile function include alterations in cellular calcium, magnesium or phosphate homeostasis. The toxic effects of acetaldehyde or the formation of fatty acid ethyl esters may cause impairment of mitochondrial oxidative phosphorylation. Alternatively, reduced amounts of heat shock proteins may result in poor assembly and protection of proteins. In acute ethanol toxicity ischaemia may occur, possibly due to increased xanthine oxidase activity or beta-adrenergic stimulation. Chronic alcohol consumption can also lead to the development of hypertension via magnesium loss and consequent alterations in peripheral vascular calcium regulation. However, these are only a few facets of a complex relationship between alcohol and the cardiovascular system.
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PMID:The effects of alcohol on the heart. 919 55

The chronic form of alcoholic skeletal myopathy is characterized by selective atrophy of Type II fibers and affects up to two thirds of all alcohol misusers. Plasma selenium and alpha-tocopherol are reduced in myopathic alcoholics compared to alcoholic patients without myopathy. Plasma carnosinase is also reduced in myopathic alcoholics, implicating a mechanism related to reduced intramuscular carnosine, an imidazole dipeptide with putative antioxidant properties. Together with the observation that alcoholic patients have increased indices of lipid peroxidation, there is evidence suggestive of free radical (i.e., unpaired electrons or reactive oxygen species) mediated damage in the pathogenesis of alcohol-induced muscle disease. Protein synthesis is a multi-step process that encompasses amino acid transport, signal transduction, translation and transcription. Any defect in one or more of the innumerable components of each process will have an impact on protein synthesis, as determined by radiolabelling of constituent proteins. Both acute and chronic alcohol exposure are associated with a reduction in skeletal muscle protein synthesis. Paradoxically, alcohol-feeding studies in rats have shown that the imidazole dipeptide concentrations are increased in myopathic muscles though alpha-tocopherol contents are not significantly altered. In acutely dosed rats, where protein synthesis is reduced, protein carbonyl concentrations (an index of oxidative damage to muscle) also decline slightly or are unaltered, contrary to the expected increase. Alcoholic cardiomyopathy can ensue from heavy consumption of alcohol over a long period of time. The clinical features include poor myocardial contractility with reduced left ventricular ejection volume, raised tissue enzymes, dilation of the left ventricle, raised auto- antibodies and defects in mitochondrial function. Whilst oxidant damage occurs in experimental models, however this issues remains to be confirmed in the clinical setting. In the rat, circulating troponin-T release increases in the presence of ethanol, a mechanism ascribed to free radical mediated damage, as it is prevented with the xanthine oxidase inhibitor and beta-blocker, propranolol. However, whilst propranolol prevents the release of troponin-T, it does not prevent the fall in whole cardiac protein synthesis, suggestive of localized ischemic damage due to ethanol.
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PMID:Oxidants, antioxidants and alcohol: implications for skeletal and cardiac muscle. 1043 May 53

Alcoholism is one of the major causes of non-ischemic heart damage. The myopathic state of the heart due to alcohol consumption, namely alcoholic cardiomyopathy, is manifested by cardiac hypertrophy, compromised ventricular contractility and cardiac output. Several mechanisms have been postulated for alcoholic cardiomyopathy including oxidative damage, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament Ca(2+ )sensitivity, and impaired protein synthesis. Despite intensive efforts to unveil the mechanism and ultimate toxin responsible for alcohol-induced cardiac toxicity, neither has been clarified thus far. Primary candidates for the specific toxins are ethanol, its first and major metabolic product - acetaldehyde (ACA) and fatty acid ethyl esters. Evidence from our lab suggests that ACA directly impairs cardiac function and promotes lipid peroxidation resulting in oxidative damage. The ACA-induced cardiac contractile depression may be reconciled with inhibitors of Cytochrome P-450 oxidase, xanthine oxidase and lipid peroxidation Unfortunately, the common methods to investigate the toxicity of ACA have been hampered by the fact that direct intake of ACA is toxic and unsuitable for chronic study, which is unable to provide direct evidence of direct cardiac toxicity for ACA. In order to overcome this obstacle associated with the chemical properties of ACA, our laboratory has used the chronic ethanol feeding model in transgenic mice with cardiac over-expression of alcohol dehydrogenase (ADH) and an in vitro ventricular myocyte culture model. The combination of both in vivo and in vitro approaches allows us to evaluate the role of ACA in ethanol-induced cardiac toxicity and certain cellular signaling pathways leading to alcoholic cardiomyopathy.
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PMID:Experimental Assessment of the Role of Acetaldehyde in Alcoholic Cardiomyopathy. 1273 61

Alcoholic cardiomyopathy is characterized by cardiomegaly, disruptions of myofibrillary architecture, reduced myocardial contractility, decreased ejection fraction, and enhanced risk of stroke and hypertension. Although several mechanisms have been postulated for alcoholic cardiomyopathy, including oxidative damage, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament Ca(2+) sensitivity, and impaired protein synthesis, neither the mechanism nor the ultimate toxin has been unveiled. Primary candidates acting as specific toxins of myocardial tissue are ethanol; its first and major metabolic product, acetaldehyde; and fatty acid ethyl esters. Acetaldehyde has been demonstrated to impair directly cardiac contractile function, disrupt cardiac excitation-contractile coupling, and contribute to oxidative damage and lipid peroxidation. Acetaldehyde-elicited cardiac dysfunction may be mediated through cytochrome P450 oxidase, xanthine oxidase, and the stress-signaling cascade. Unfortunately, the most direct approach that can be used to examine toxicity is hampered by the fact that direct intake of acetaldehyde is highly toxic and unsuitable for long-term study. To overcome this obstacle, transgenic mice have been used to alter artificially ethanol/acetaldehyde metabolism, resulting in elevated acetaldehyde concentrations after ethanol ingestion. In this review, we summarize results obtained with the use of transgenic animal models to elucidate the role of acetaldehyde in the mechanism of action in alcoholic cardiomyopathy.
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PMID:Ethanol and acetaldehyde in alcoholic cardiomyopathy: from bad to ugly en route to oxidative stress. 1528 11