Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Mol Aspects Med 1988
PMID:Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. 306 25

Chronic pancreatitis is characterized by inflammation and fibrosis leading to tissue destruction; in industrialized nations, alcohol abuse is the cause of 70-80% of cases of pancreatitis in adults. The purpose of the current work was to determine whether free radical adducts are produced by the pancreas during the early phases of chronic exposure to ethanol. Accordingly, rats were chronically fed ethanol using the model of continuous enteral infusion developed by Tsukamoto et al.[Am. J. Physiol. 247: R595-R599 (1984)]. Histological evaluation revealed only mild acinar steatosis and spotty necrosis after 4 weeks of alcohol treatment; the pancreatic enzymes lipase and amylase were not elevated. Furthermore, no fibrosis was detected, nor were there differences in pancreatic collagen alpha 1(l) mRNA levels between the dietary control and ethanol-treated groups. After 4 weeks, rats were injected with the spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (1 g/kg intravenously), and pancreatic secretions were collected over a 4-hr period. A six-line free radical adduct spectrum indicative of a carboncentered free radical was detected in pancreatic secretions and in Folch extracts of pancreatic tissue by electron spin resonance spectroscopy. Control experiments ruled out ex vivo radical formation. This study represents the first detection of radical adducts in pancreatic secretions. When [13C]ethanol (3 g/kg intragastrically) was administered, a definitive 12-line spectrum was detected in pancreatic secretions, demonstrating that the alpha-hydroxyethyl radical adduct was formed in the pancreas from [13C]ethanol. Interestingly, only a six-line signal was detected in tissue extracts under these conditions. Free radicals, therefore, are formed in the pancreas during the early phases of chronic alcohol intake in rats before the development of overt pathology.
Mol Pharmacol 1996 Sep
PMID:Detection of alpha-hydroxyethyl free radical adducts in the pancreas after chronic exposure to alcohol in the rat. 879 7

After 10 months of alcohol abstinence a malnourished alcoholic patient improved his nutritional status. The analysis of peripheral blood lymphocyte response to mitogenic stimulation with the antibody anti-CD3 and of the fatty acid composition of the (poly)-phosphoinositide fraction derived from lymphocytes revealed: 1) a similar [3H]-thymidine uptake as in control (non-drinker) subjects; 2) a similar relative molar content of the main fatty acids in the (poly)-phosphoinositides as in control subjects. Alcohol abstinence can normalize both the parameters, which are greatly altered during alcohol abuse. This suggests a link between nutritional status and lymphocyte responsiveness via phosphoinositide fatty acid composition.
Biochem Mol Biol Int 1996 May
PMID:Normalization of immune response and phosphoinositide fatty acid composition of peripheral blood lymphocytes in an alcoholic patient after alcohol abstinence. 879 64

Fatty acid ethyl ester synthase metabolizes ethanol non-oxidatively in those extrahepatic organs most commonly damaged by alcohol abuse. This study was designed to purify human myocardial fatty acid ethyl ester synthase (FAEES)/carboxylesterase from human heart. The enzyme was purified to homogeneity after chromatography over DEAE-cellulose, Sephadex G-100 and hydroxylapatite. The homogenous enzyme, 62 kDa, has both synthase and carboxylesterase activities. The N-terminal amino acid sequence of the first 17 residues of the purified enzymes were 88% homologous to that of the carboxylesterase from rat liver and adipose tissue. Antibody was raised against pure synthase/carboxylesterase cross-reacted with human cytosolic and microsomal fractions. With a constant oleic acid concentration of 0.25 mM, a calculated apparent Km and Vmax for ethanol were 0.30 M and 3700 nmol/mg protein/h., respectively. With constant ethanol concentrations of 1.2 M, the activity increased with the concentration of oleic acid to 0.17 mM, plateau to 0.25 mM. Because synthase/carboxylesterase esterifies free fatty acids with ethanol to produce its esters with potentially toxic effects, it may now be feasible to establish a link between alcohol consumption and end-organ damage.
J Mol Cell Cardiol 1996 Sep
PMID:Purification and characterization of human heart fatty acid ethyl ester synthase/carboxylesterase. 889 61

Low birth weight in combination with a large placenta predicts human hypertension. The pathophysiological link remains unclear, but glucocorticoid excess impairs fetal growth and leads to offspring hypertension. A key controller of fetal glucocorticoid exposure and local tissue availability is 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). The activity of placental 11beta-HSD2 correlates with fetal growth in animals and humans. Ethanol abuse and smoking are known to retard fetal growth which may relate to altered glucocorticoid action or dynamics. This study has examined whether nicotine or ethanol modulate glucocorticoid action in the placenta or fetus by inhibiting 11beta-HSD2, using clonal cell cultures, freshly isolated dually perfused intact human placentas and placentas from in vivo treated rats. No significant effect on the activity of 11beta-HSD2 by pathophysiologically relevant nicotine or ethanol concentrations was observed. The mechanism of action of nicotine and ethanol relevant to reduced fetal growth requires further study.
J Steroid Biochem Mol Biol
PMID:Lack of effect of nicotine or ethanol on the activity of 11beta-hydroxysteroid dehydrogenase type 2. 945 96

Effects of ethanol treatment and its withdrawal on insulin binding to isolated rat Leydig cells were studied. Mature rats were given ethanol by gastric intubation for 30 days at a dose of 3.0 g/kg body weight, twice daily, as a 25% (v/v) aqueous solution and treatment was withdrawn for the subsequent 30 days in an another group. Ethanol treatment markedly increased serum insulin and reduced the 125I-insulin binding to Leydig cells and the activities of Leydig cellular steroidogenic enzymes such as 3 beta-HSD and 17 beta-HSD. Withdrawal of ethanol treatment restored these changed values to their normal levels. The results suggest the possible involvement of subnormal insulin actions, as that of LH, in the ethanol-induced impairment of Leydig cellular steroidogenesis and the resulting hypoandrogenization associated with alcohol abuse.
Biochem Mol Biol Int 1998 Jun
PMID:Effects of ethanol ingestion on insulin binding to rat Leydig cells. 963 27

Endothelin-1 (ET-1) and nitric oxide are emerging key mediators in the maintenance of mucosal homeostasis, but little is known about these substances in soft oral tissue with alcohol abuse. Hence, we examined the expression of ET-1 and activity of the constitutive nitric oxide synthase (NOS) in buccal mucosa of rats subjected to chronic ethanol diet. The immunometric assays revealed the buccal mucosal level of ET-1 in the controls at 40.2 pg/mg protein and showed a 4.1-fold increase with alcohol diet to 166.2 pg/mg protein. The NOS assays established that comparing to the controls, the alcohol diet group exhibited a 57% decrease in buccal mucosal NOS activity. Moreover, the expression of ET-1 showed an inverse correlation (r = -0.75) with the extent of the induced changes in NOS. The results suggest that an increase in vasoconstrictive ET-1 levels combined with a loss of compensatory action by the constitutive NOS may be responsible for the weakening of oral mucosal defenses in alcoholics.
Biochem Mol Biol Int 1998 Jul
PMID:Alterations in buccal mucosal endothelin-1 and nitric oxide synthase with chronic alcohol ingestion. 971 90

The chronic consumption of alcohol has proven detrimental to heart tissue and can lead to alcohol-induced heart muscle disease, a condition which may result in arrhythmias, cardiomegaly, and congestive heart failure. A search for the molecular mechanism underlying observed alcohol-induced end-organ damage, such as that seen in heart, has lead to the discovery of a nonoxidative pathway for the metabolism of alcohol in several human tissues including heart, brain, pancreas, and liver. It has been revealed that nonesterified fatty acids are esterified with ethanol to produce fatty acid ethyl esters (FAEE), neutral molecules which can accumulate in mitochondria and impair cell function. The observation that FAEEs are synthesized at high rates in the heart, and other organs that lack oxidative ethanol metabolism, provides a plausible link between the observed tissue damage, the ingestion of alcohol, and the subsequent development of alcohol-induced heart muscle disease. The synthesis of FAEEs are catalyzed by FAEE synthase enzyme, four of which have been characterized and purified to homogeneity from the human myocardium. Further analysis of these FAEE synthase enzymes opens up a new possibility to characterize and map a gene for alcohol-induced end-organ damage, such as that observed in heart and other organs. FAEEs have been found to be important metabolites of alcohol and are most commonly accumulated in those organs which are damaged by alcohol abuse, i.e. heart. It may now be important to establish a genetic link between alcohol abuse and alcohol-induced heart muscle disease in order to understand the mechanism of alcohol-induced cardiomyopathy.
J Mol Cell Cardiol 1998 Nov
PMID:Fatty acid ethyl esters: potentially toxic products of myocardial ethanol metabolism. 992 83

Autoantibodies against soluble liver enzymes have been reported among alcoholics, but the targets of self-reactivity toward membrane proteins of the liver have not been characterized. Previously, among alcoholics, we found antibodies against ethanol-derived radical protein adducts that are dependent on cytochrome P-4502E1 (CYP2E1) for their formation. To further investigate autoantibodies against cytochrome P-450s during alcohol abuse, sera of rats chronically treated with ethanol in the total enteral nutrition model and sera from alcoholics with or without alcohol liver disease and from control subjects were analyzed by enzyme-linked immunosorbent assay and Western blotting for the presence of IgG against rat and human CYP2E1, rat CYP3A1, and human CYP3A4. A time-dependent appearance of IgG against rat CYP3A1 and CYP2E1 was evident during chronic ethanol feeding of rats. Anti-CYP2E1 reactivity showed positive correlation with the levels of hepatic CYP2E1 and was inhibited by the CYP2E1 transcriptional inhibitor chlormethiazole. Screening of the human sera by enzyme-linked immunosorbent assay revealed reactivity against CYP3A4 and CYP2E1 in about 20 to 30% and 10 to 20% of the alcoholic sera, respectively. No difference were noted between sera from alcoholics with or without hepatitis C virus infection, and only very little reactivity was seen in sera from control subjects. Western blotting analysis revealed anti-human CYP2E1 reactivity in 8 of 85 alcoholic sera and 3 of 58 control sera, whereas anti-CYP3A4 reactivity was detected in 18 of 85 alcoholic sera and 4 of 58 control sera, which were different from the sera reactive with CYP2E1. Immunoblot reactivity of CYP3A4-positive alcoholic sera was found against glutathione-S-transferase fusion proteins containing truncated forms of CYP3A4, and such sera were also able to immunoprecipitate in vitro translated CYP3A4. Seven of eight sera showed reactivity toward domains C-terminal of position Ser281, and 1 of 8 sera recognized autoepitopes within the region Thr207-Ser281. These findings indicate that alcoholics develop autoantibodies against CYP2E1 and CYP3A4 that the CYP3A4 C-terminal domain is a target for the autoantibody reactions among a subset of alcoholics. The novel finding of CYP3A4 autoantibodies and their significant expression among alcoholics warrants further investigation. Attention should be given to immune toxicity associated with CYP3A4 autoantibodies and cases of alcohol abuse that are accompanied by exposure to drugs and substances that are CYP3A substrates.
Mol Pharmacol 1999 Feb
PMID:Autoantibodies against cytochromes P-4502E1 and P-4503A in alcoholics. 992 12

Ethanol is a major health concern, with neurotoxicity occurring after both in utero exposure and adult alcohol abuse. Despite a large amount of research, the mechanism(s) underlying the neurotoxicity of ethanol remain unknown. One of the cellular aspects that has been investigated in relationship to the neuroteratogenicity and neurotoxicity of ethanol is the maintenance of calcium homeostasis. Studies in neuronal cells and other cells have shown that ethanol can alter intracellular calcium levels and affect voltage and receptor-operated calcium channels, as well as G protein-mediated calcium responses. Despite increasing evidence of the important roles of glial cells in the nervous systems, few studies exist on the potential effects of ethanol on calcium homeostasis in these cells. This brief review discusses a number of reported effects of alcohol on calcium responses that may be relevant to astrocytes' functions.
Mol Neurobiol 1999 Feb
PMID:Effects of ethanol on calcium homeostasis in the nervous system: implications for astrocytes. 1032 69


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