Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.1.1.1 (alcohol dehydrogenase)
 9,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Methyl pyrazole (4-MP, a specific inhibitor of alcohol dehydrogenase) reduced ethanol elimination by 30-50% and completely removed the ethanol-induced inhibition of galactose elimination in 2 control subjects. Ethanol elimination was accelerated in 2 alcoholics with adequate nutrition, but the effect of 4-MP was comparable to that in controls. In 2 other alcoholic subjects, who reported poor nutritional intake, intermediate rates of ethanol elimination were observed and 4-MP had almost no effect on ethanol or galactose elimination. These results suggest that alcohol abuse may result in an increased contribution to ethanol elimination by pathways other than that involving alcohol dehydrogenase (ADH) and that the decreased contribution from ADH, possibly potentiated by inadequate nutrition, may diminish the ethanol-induced shift in the NAD-coupled redox state. Since liver damage produced by alcohol abuse is believed to be related to changes from the normal redox state caused by ethanol, these results may explain why alcoholic liver damage is uncommon in alcoholics living on a marginal diet. Since 4-MP effectively eliminates the ethanol-induced shift in the redox state, a therapeutic trial with 4-MP in alcoholics with a high risk for liver disease is indicated.
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PMID:Ethanol and galactose metabolism as influenced by 4-methylpyrazole in alcoholics with and without nutritional deficiencies. Preliminary report of a new approach to pathogenesis and treatment in alcoholic liver disease. 0 33

The pharmacogenetic differences among individuals in their capacity to metabolize ingested alcohol are possibly responsible for the large inter-individual and inter-ethnic variations observed in the outcome of alcohol use and misuse. Based on results of adoption, twin, and family studies it is now widely accepted that the vulnerability to alcoholism is determined by genetic factors as well as by environment. There is a constant search for biological markers and specific genes which could identify individuals genetically predisposed to alcohol abuse and alcoholism. Numerous 'candidate genes' for alcoholism have been suggested including the alcohol metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Both ADH and ALDH exhibit genetic heterogeneity. An atypical form of ADH (ADH2), which contains a variant beta 2 subunit instead of the usual beta 1 subunit, differs substantially from the usual form in its kinetic properties and is found more frequently among the Japanese, Chinese and other Mongoloid populations than in Caucasoids and Negroids. A widely prevalent genetic polymorphism has been observed for ALDH; about 50% of Japanese and Chinese livers possess an inactive ALDH (ALDH2 isozyme) whereas none of the Caucasian or Negroid populations show this isozyme abnormality. These metabolic polymorphisms seem to contribute to differences in the in vivo elimination rate of ethanol and acetaldehyde, and may explain differences in alcohol-related behaviour and its disease outcome. Taken together, Orientals who possess an atypical ALDH2 gene are more sensitive to acute responses to alcohol, tend to be discouraged from drinking alcohol, and consequently are at lower risk of developing alcohol-related disorders. However, more work is needed to support these findings. Recent advances in molecular genetics have made it possible to analyze directly the human genome. This may help in a better understanding of the complex genetic and environmental factors in alcohol abuse by providing prospects for identification of gene loci which may be responsible for predisposition to, and protection from, alcoholism.
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PMID:Pharmacogenetics of alcohol metabolism and alcoholism. 130 43

The present paper is devoted to overview the basic concepts of ethanol-induced hepatic injury and therapeutic modalities by which alcoholic liver disease can be alleviated. The role of alcohol dehydrogenase of both hepatic and gastric origin as well as the importance of the number one metabolite acetaldehyde are discussed, furthermore the effects of microsomal ethanol oxidizing system are also described. The features of the major clinicopathological consequences of alcohol abuse fatty liver, alcoholic hepatitis are briefly outlined, and the basic pathogenetic mechanisms that lead to cirrhosis--cell necrosis, regeneration and fibroplasia--are shown. The understanding of the pathophysiology of alcohol-induced liver injury may improve the therapy with drugs and nutritional factors, and allow successful prevention through the early recognition of heavy drinkers before their social or medical disintegration. In the management of alcoholic liver diseases, among the true hepatoprotective agents a naturally occurring flavonoid silymarin and an active methyl-donor metabolite S-adenosyl-L-methionine seem to be promising. An antifibrotic treatment with colchicine might also be of importance. Further prospective, well-designed, controlled clinical trials are still warranted to evaluate real efficacy of these drugs. The hepatic consequences of alcohol abuse may be treatable, however, prevention would be the true resolution of the major global health problem of alcoholism.
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PMID:Pathogenesis and management of alcoholic liver injury. 134

Two types of factors can theoretically modulate alcohol metabolism toward increased acetaldehyde production. These factors are the following: (a) individual, genetically determined isoenzymes with distinct catalytic properties, and (b) modifications of enzyme activity induced by alcohol itself or liver damage. To investigate the respective roles of these factors in white individuals, we studied the alcohol dehydrogenase phenotype, together with liver alcohol dehydrogenase and aldehyde dehydrogenase activities, in 161 patients. Patients with alcoholic cirrhosis (n = 31) were compared with three types of controls: patients with nonalcoholic cirrhosis (n = 25) and excessive (n = 62) and moderate drinkers (n = 43) without liver disease. No association between alcohol dehydrogenase-3 phenotype and alcoholic cirrhosis was found. The prevalence of atypical alcohol dehydrogenase in the four groups was less than 1%. Patients with cirrhosis, regardless of its cause, had significantly lower alcohol dehydrogenase activity than the patients without cirrhosis (p less than 0.05 and p less than 0.01 vs. excessive and moderate drinkers, respectively). Among the noncirrhotic patients, alcohol dehydrogenase activity was significantly lower in the excessive drinkers than in the moderate drinkers (p less than 0.001). Aldehyde dehydrogenase activity was not different between cirrhosis-free excessive and moderate drinkers; in contrast, compared with these two groups, it was significantly lower in the two cirrhosis groups (p less than 0.01). These results suggest that no phenotypic pattern of alcohol dehydrogenase-3 associated with alcoholic cirrhosis in white patients exists, that liver alcohol dehydrogenase activity falls as a consequence of both alcohol abuse and cirrhosis and that liver aldehyde dehydrogenase activity is unaffected by alcohol abuse and only falls after the onset of cirrhosis.
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PMID:Polymorphism of alcohol dehydrogenase, alcohol and aldehyde dehydrogenase activities: implication in alcoholic cirrhosis in white patients. The French Group for Research on Alcohol and Liver. 832 17

Mounting evidence from various fields of research links the oxidation product of alcohol, acetaldehyde, with the development of alcohol abuse-related pathology. One factor governing the production of acetaldehyde is the genetically determined pattern of class I alcohol dehydrogenase isoenzymes, consisting of "fast" beta 2 and gamma 1 and "slow" beta 1 and gamma 2 subunits. Alcoholics carrying the beta 2 and gamma 1 genes might, therefore, be more susceptible to alcohol-related liver disease. To verify this hypothesis we developed a method based on the polymerase chain reaction and restriction enzyme digestion in order to genotype individuals with respect to their alcohol dehydrogenase isoenzyme pattern. In a total of 100 caucasian individuals the following genotypes were determined: beta 1 beta 1, 92; beta 1 beta 2, 8; beta 2 beta 2 0; gamma 1 gamma 1, 38; gamma 1 gamma 2, 51; gamma 2 gamma 2, 11. No statistically significant differences in the distribution of isoenzymes were detectable between alcoholics with liver disease, patients with non-alcohol abuse-related liver disease, patients with rheumatoid arthritis and healthy controls.
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PMID:[Determination of alcohol dehydrogenase genotype: no correlation between isoenzyme pattern and liver cirrhosis]. 175 48

Little is known about factors determining individual susceptibility to the physical complications of alcohol abuse but genetically determined differences in ethanol metabolism may be important. The oxidative metabolism of alcohol is catalyzed by alcohol and aldehyde dehydrogenase. Polymorphisms have been observed at two of the five loci encoding alcohol dehydrogenase subunits: ADH2 (producing three beta subunits) and ADH3 (producing two tau subunits) and also at the locus encoding the metabolically important form of aldehyde dehydrogenase, ALDH2. We have compared ADH2, ADH3 and ALDH2 allele frequencies in patients with alcohol-related cirrhosis (n = 59) and chronic pancreatitis (n = 13) with 79 local healthy control subjects. The different alleles were detected with allele-specific oligonucleotide probes after amplification of leukocyte DNA by the polymerase chain reaction. All patients and all but one control subject were homozygous ADH2*1, encoding the beta 1 subunit. No ADH2*3 alleles were detected. All 34 patients and 39 control subjects tested were homozygous ALDH2*1 encoding the active enzyme. ADH3 allele frequencies were different in patients and control subjects. ADH3*1 frequency: control subjects, 55.1%; cirrhotic patients, 62.7%; chronic pancreatitis patients, 65.4%. The difference between the patient groups combined and the control subjects was significant (p less than 0.05; G-test of Sokal and Rohlf) if it was assumed that the allele frequency in our control population was a reasonable estimate of our local population allele frequency. These results suggest that genetically determined differences in alcohol metabolism may, in part, explain predisposition to alcohol-related end-organ damage.
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PMID:Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage. 193 84

Lipoperoxidation, a degradative process of membranous polyunsaturated fatty acids, has been suggested to represent an important mechanism in the pathogenesis of ethanol toxicity on the liver and possibly also on the brain. Catalysis by transition metals, especially iron, is involved in the biosynthesis of free radicals contributing to lipid peroxidation. Although the exact nature of the redox-active iron implicated in this catalysis is still unknown, it has been well established that lipid peroxidation can be prevented in vitro by iron chelators such as desferrioxamine. Deprivation of redox-active iron through desferrioxamine inhibits by about 50% the microsomal oxidation of ethanol in vitro and reduces very significantly in vivo the overall ethanol elimination rate in rats. Administration of desferrioxamine together with ethanol also reduces the ethanol-induced disturbances in the antioxidant defense mechanisms of the hepatocyte. It also reduces in mice both the severity of physical dependence on ethanol and lethality following the acute administration of a narcotic dose of ethanol. Chronic overloading of rats with iron results, on the opposite, in an increased rate of ethanol elimination, although alcohol dehydrogenase and catalase activities are reduced and cytochrome P-450 depleted in the liver of such iron-overloaded animals. The magnitude of the ethanol-induced increase in lipid peroxidation and decrease in the major membranous antioxidant, alpha-tocopherol, is exacerbated in iron-overloaded rats. Several disturbances of iron metabolism have been reported in human alcoholics. Their contribution to ethanol toxicity appears very likely in the case of hepatic siderosis associated with alcohol abuse. Ethanol could however disturb iron metabolism even in the absence of gross abnormalities of the total iron stores. It is suggested that ethanol intoxication could increase cellular redox-active iron, thus contributing to an enhanced steady-state concentration of reactive-free radicals. This oxidative stress would lead to lipoperoxidative damage and cellular injury.
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PMID:Involvement of iron and iron-catalyzed free radical production in ethanol metabolism and toxicity. 303 5

Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.
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PMID:Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. 306 25

Since red cells transport and metabolize acetaldehyde in vivo, the effects of acetaldehyde on human red cell enzyme activities were studied. Incubation of intact red cells or undiluted red cell lysates at 37 degrees C for 4 h with 1-10 mmol/l acetaldehyde decreased only GOT, GPT and aldolase activities among the 26 enzymes tested. No inhibition occurred at 4 degrees C or when acetaldehyde was incubated with dilute hemolysates. Incubation of lysates with other reducing substrates or with acetate inhibited aldolase but not GOT or GPT. Preincubation of lysates with cyanate or fluoride markedly decreased acetaldehyde-mediated transaminase inhibition but not aldolase inhibition. Addition of pyridoxal phosphate, the vitamin B6 transaminase coenzyme, to GOT and GPT assay mixes did not reverse acetaldehyde-mediated transaminase inhibition. These findings suggest that acetaldehyde-mediated aldolase inhibition results from oxidation of acetaldehyde while transaminase inhibition results from nonoxidative acetaldehyde metabolism. When 100-200 mumol/l acetaldehyde is added to lysates at 2-h intervals and when lysates are incubated with ethanol, alcohol dehydrogenase and an NAD-regenerating system, enzyme inhibition occurs at acetaldehyde levels approaching those seen in vivo. Thus, the role of acetaldehyde-mediated enzyme inhibition in the toxicity of alcohol abuse warrants further study.
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PMID:Effects of acetaldehyde on human red cell metabolism: evidence for the formation of enzyme inhibitors. 341 86

Oxidative pathways of alcohol metabolism such as alcohol dehydrogenase usually are not present in human blood and therefore clinical studies correlating ethanol metabolism with alcohol abuse syndromes have not been performed. To assess the activity of nonoxidative ethanol metabolism in blood, we assayed for the activity of fatty acid ethyl ester synthase, a pathway recently described as abundant in the human organs most commonly damaged by alcohol. Indeed, peripheral human leukocytes contain detectable fatty acid ethyl ester synthase activity: 1.2 X 10(6) leukocytes from 10 ml blood catalyze the synthesis of ethyl oleate at 1.4 nmol/4 hr. The reaction is linear with respect to cell number and expended time; Km oleate = 600 microM, Km ethanol = 600 mM. DEAE cellulose chromatography partially purifies synthase activity into a minor and major form (activity ratio = 10/1). Thus, gene products exist in human blood that recognize ethanol and whose biological activity is conveniently assayable for clinical investigations of alcohol metabolism and abuse.
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PMID:Nonoxidative ethanol metabolism in human leukocytes: detection of fatty acid ethyl ester synthase activity. 382 9


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