Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0016382 (flushing)
 6,387 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nearly half of all Orientals exhibit aversive symptoms, such as "Oriental flushing" or palpitation, during alcohol consumption. This high alcohol sensitivity among Orientals has been attributed to a highly prevalent polymorphism in low Km aldehyde dehydrogenase (ALDH2). In the present study, we attempted to develop a reliable questionnaire method to probe the frequency of alcohol drinking-related symptoms to estimate the ALDH2 genotype. Four-hundred twenty-four male and 100 female workers provided blood samples for polymerase chain reaction analysis and completed the questionnaire. We performed a stepwise logistic regression analysis to discriminate between the typical homozygote (ALDH2*1/*1) and the atypical heterozygote (ALDH2*1/*2) in male subjects. Because of the limitation in the sample size for ALDH2*2/*2, this genotype was not included in the analysis. Results revealed that only three symptoms (facial flushing, flushing elsewhere, and palpitation) were enough to correctly predict the ALDH2 genotypes in approximately 89% of all subjects. The present questionnaire method (ALcohol Sensitivity screening Test; ALST) takes a little time and effort for the genotype determination, and may be especially useful in epidemiological studies with a large sample size or with subjects from whom DNA samples are not available.
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PMID:Development of a questionnaire method to discriminate between typical and atypical genotypes of low Km aldehyde dehydrogenase in a Japanese population. 980 21

The characteristics of alcohol-induced flushing response were studied in some Siberian Native populations (Chukchi, Eskimo, Jakuts, Udege, and Nanaian). Flushing peculiarities were estimated and the interrelationship with drinking patterns, the ethanol patch test (EPT), and somatic disorders were analyzed. Frequency of flushing response varied from 9.0% to 66.7%, and was more often apparent among females. Only the Nanaian demonstrated typical flushing, which did not allow them to consume high doses of alcohol. In the rest of the populations flushing was "atypical," i.e., appearing sometimes after high doses of alcohol but not interrupting alcohol drinking, and not associated with a positive EPT. Direct genotyping in DNA samples of Chukotka Natives did not reveal atypical allele aldehyde dehydrogenase (AIDH 2/2). Frequencies of alcohol problems, alcohol dependence symptoms, and somatic disorders (arterial hypertension, silent ischemia, diffuse liver lesions, and noncalculous cholecystitis) were higher among atypical flushers compared to nonflushers (p < 0.05-0.01). The mechanism of the observed atypical flushing response is unknown. We speculate on its hereditary nature, since flushing alcoholics, compared to nonflushers, reported that their parents had flushing responses significantly more often. Further studies are required.
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PMID:Flushing response and its role in alcohol disease in Siberian populations. 1009 24

Alcohol and histamine metabolic pathways in the body have the common enzymes aldehyde dehydrogenase and aldehyde oxidase. The metabolite of ethanol, acetaldehyde, can effectively compete with the metabolites of histamine, methylimidazole acetaldehyde, and imidazole acetaldehyde. At the periphery, alcohol and acetaldehyde liberate histamine from its store in mast cells and depress histamine elimination by inhibiting diamine oxidase, resulting in elevated histamine levels in tissues. Histamine mediates alcohol-induced gastric and intestinal damage and bronchial asthma as well as flushing in Orientals. On the other hand, alcohol provokes food-induced histaminosis and histamine intolerance, which is an epidemiological problem. There are many controversial reports concerning the effect of H2 receptor antagonists on ethanol metabolism and the activity of alcohol dehydrogenase in the stomach. In addition, alcohol affects histamine levels in the brain by modulating histamine synthesis, release, and turnover. Histamine receptor antagonists can affect ethanol metabolism and change the sensitivity of animals to the hypnotic effects of alcohol. In contrast to other neurotransmitters, the involvement of the brain histamine system in the mechanisms of the central actions of alcohol and in the pathogenesis of alcoholism is poorly studied and understood.
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PMID:Alcohol-histamine interactions. 1034 73

High alcohol sensitivity common among Orientals is mainly due to genetic polymorphism in the low K(m) aldehyde dehydrogenase (ALDH2) gene. The relation of the ALDH2 genotype to alcohol sensitivity and drinking behavior was investigated in a Japanese occupational population. The frequency of alcohol-associated symptoms generally increased in the order of the typical homozygote, heterozygote, and atypical homozygote. Both drinking frequency and amounts of alcohol consumption were also significantly affected by the polymorphism. Polymorphism in the alcohol dehydrogenase beta-subunit (ADH2 gene) appeared to contribute to skin flushing post-alcohol exposure but not to alcohol drinking behavior. Multivariate analysis revealed that high alcohol consumption, the ALDH2*1/*1 genotype, and high daily hassles levels significantly contribute to the prevalence of those with a high problem-drinking score in an occupational population. In the study to assess the effects of the ALDH2 polymorphism and alcohol use on the induction of chromosome alterations in peripheral lymphocytes, we found that lymphocytes from habitual drinkers with the atypical ALDH2 genotypes had significantly higher frequencies of sister-chromatid exchange (SCE) than those from the typical ALDH2 genotype. We also measured acetaldehyde reversibly bound to hemoglobin (HbAA). In volunteers with the ALDH2*1/*2 genotype, the HbAA levels increased immediately after the drink and the elevated levels persisted up to 48 h. Among male workers, HbAA levels were significantly correlated with the recent alcohol consumption levels in both the ALDH2*1/*1 and ALDH2*1/*2 genotypes. However, the slope was much steeper in the ALDH2*1/*2 than in the ALDH2*1/*1. SCE and HbAA may be utilized as a good biomarker for health problems in the atypical ALDH2 genotype. Further extensive studies are required for evaluation of the interactive effects of genetic and environmental factors on alcohol-related health problems.
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PMID:[Genetic factors which regulate alcohol drinking behavior and their effects on health status]. 1047 85

To assess clinical availability of the aldehyde dehydrogenase (ALDH) 2 gene polymorphism to detect alcohol sensitivity among a Japanese population, we determined the ALDH 2 genotypes and also compared to an ethanol patch test in 119 young Japanese. Their alcohol sensitivity was evaluated by a questionnaire on the frequency of alcohol-associated symptoms when they drink. Genomic DNA was extracted from blood samples and amplified by polymerase chain reaction (PCR). PCR primers were flanking the polymorphic region in exon 12 of the ALDH 2 gene. The distribution of the typical homozygote, the heterozygote and the atypical homozygote was 63.9, 31.9 and 4.2%, respectively. Gene frequencies of the typical and atypical alleles calculated from the genotype frequencies were 0.80 and 0.20. The atypical genotypic homozygotes were positively associated with facial flushing symptom, but not with positive response for ethanol patch test. These results indicate that ALDH 2 genotypes determination is essential to detect alcohol sensitivity whereas the ethanol patch test has some limitations.
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PMID:Analysis of aldehyde dehydrogenase 2 gene polymorphism and ethanol patch test as a screening method for alcohol sensitivity. 1050 2

The experimental approach has been used to study successfully the relationship between the polymorphism of aldehyde dehydrogenase 2 and the flushing syndrome. In the present study, a probabilistic approach was used to analyse this relationship. Using cross-impact analysis and experimental data, the probability of the occurrence of flushing, the extent by which ALDH2*2/*2 enhances flushing more than ALDH2*1/*2, the extent by which ALDH2*1/*1 enhances non-flushing more than ALDH2*1/*2, etc. can be calculated. Two examples are given to show the potential use of cross-impact analysis.
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PMID:Application of cross-impact analysis to the relationship between aldehyde dehydrogenase 2 allele and the flushing syndrome. 1068 78

Acetaldehyde (AcH), the first metabolite of ethanol (EtOH), is a chemically reactive and pharmacologically active compound. The author has been engaged in the study of AcH in cooperation with many researchers for three decades. We have found many biological actions of AcH which cause cardiovascular symptoms after drinking and also inhibited EtOH absorption via the canine and rat intestinal tract. This report covers the following five points. 1. The subjects were classified into a non-flushing group and a flushing group, according to the degree of facial flushing after drinking 200 ml of Sake (Japanese rice wire) at a rate of 100 ml per 5 min. Blood EtOH profile was much the same in both groups, yet peak blood AcH concentration in the flushing group was significantly higher than that in the non-flushing group. All subjects in the flushing group showed marked flushing and an increase in pulse rate after drinking, but these symptoms were not apparent in the non-flushing group. These results suggested that cardiovascular symptoms were caused by AcH itself. 2. Urinary excretions of both norepinephrine and epinephrine increased in the flushing cases after drinking Sake in comparison with those who drank the same volume of water. However, these catecholamines did not change in the non-flushing group. These results suggested that it is catecholamines released from the sympathetic nerve end or the adrenal medulla by AcH which caused an increase in pulse rate. 3. Bradykinin is released from high molecular kininogen by activated kallikrein and acts to dilate distal blood vessels and raise permeability in tissues. On the other hand, kallidin is released from low molecular kininogen by activated glandular kallikrein and its action is weaker than that of bradykinin. Blood low molecular kininogen levels in the flushing group decreased gradually after drinking and were mutually related to the blood AcH concentrations. But levels in the non-flushing group showed no difference before and after drinking. The decrease in low molecular kininogen levels indicates that kallidin released from glandular kallikrein exists in the glandular tissues such as the kidneys, sweat glands, saliva glands, etc. We hypothesize that kallikrein activated by AcH in the sweat glands produces kallidin which cause vessels around the glands to dilate, and flushing of the face and the whole body occurs due to escalation of the sphere of dilatation of blood vessels. 4. A isolated 30 cm length of the canine jejunum segment with intact vascular supply was performed. After pretreatment with cyanamide (CY), a potent inhibitor of aldehyde dehydrogenase, or pyrazole (PY), a potent inhibitor of alcohol dehydrogenase, a 17% EtOH solution (0.4 g/kg) was administered into the jejunum segment, and 150 min after the administration of EtOH, the fluid from the segment was collected to determine its volume and EtOH concentration. The CY-pretreatment group, in which an extremely high AcH concentration developed, in comparison with the control and PY-pretreatment groups, showed a gradual increase of portal blood EtOH, a 25% reduction in the amount of absorbed EtOH, and an 85% smaller absorption rate constant value (Ka value). These facts indicate that the presence of a high AcH concentration in the blood results in a reduction of EtOH absorption and retardation of EtOH reaching the systemic circulation. The rapid reduction of portal blood flow and lower EtOH level in the portal vein observed in the CY group, in comparison with the other groups, also indicate that the reduction of EtOH permeability through the absorption site to the blood is an important retarding factor induced by AcH. 5. After segmenting a 20 cm length of rat intestine, cannulae for EtOH perfusion were inserted into each end of the intestine segment. Perfusion of EtOH solution (4%) was performed for 30 min at steady rate, beginning 60 min after pretreatment with CY and/or PY. The blood EtOH and AcH concentrations in the f
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PMID:[Biological actions of acetaldehyde]. 1072 60

Using a dipole tracing method based on the two-dipole model, the purpose of the present study was to investigate alcohol-induced changes in the alpha band of electroencephalogram (EEG) and its equivalent current dipoles (ECDs) in 12 healthy male volunteers, who were genetically typed for mitochondrial aldehyde dehydrogenase-2 (ALDH2). The alpha power and the mean interval dipolarity, which represents the goodness of fit of alpha EEG with the two-dipole model, increased at 30 min after 0.75 ml/kg of alcohol ingestion, when breath alcohol concentration showed its peak. However, the location of ECDs and distribution of alpha EEG did not change after alcohol ingestion. These findings indicate that alcohol enhances alpha EEG but does not change the location of its electrical sources. Interestingly, the time course of alcohol-induced EEG changes differed significantly according to the aversive flushing reaction after its intake. From 60 to 120 min, the non-flushing group which had homozygous ALDH2* 1 (active type) displayed significant increase not only in the alpha power but also in the interval dipolarity compared to the baseline, whereas the flushing group with heterozygous ALDH2*1/2*2 (inactive type) did not exhibit this significant increase. The difference in the time course was discussed from the viewpoint of the protective effect of ALDH2*2 allele against the risk for alcoholism. These results suggest that the dipole tracing method could provide an alternative neurophysiological marker for the risk for alcoholism.
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PMID:Dipole estimation of alpha EEG during alcohol ingestion in males genotypes for ALDH2. 1095 50

Multiple forms and gene loci of human alcohol dehydrogenase (ADH EC: 1.2.1.3) and aldehyde dehydrogenase (ALDH, EC: 1.2.1.3) in the major pathway of alcohol metabolism have been found and characterized in the last two decades. With the coenzyme NAD, these enzymes catalyze the reversible conversion of organic alcohols to ketones or aldehydes, and aldehyde to acetic acid. The ADH genes are mapped to chromosome 4p21-25, but the ALDH genes are localized at different chromosomes. The cytochrome P450 2E1 (CYP2E1) gene, which is mapped to chromosome 10q24.3-qter contributes also the conversion of ethanol to acetaldehyde. Genetic polymorphisms have been reported in these alcohol metabolizing enzymes. The metabolisms of alcohol and acetaldehyde in liver and blood after drinking alcohol are thought to be influenced by the interactive action of these enzymes. Amongst the five major classes of the ADH subunits (alpha, beta, gamma, pi, chi, sigma), beta and gamma subunits show genetic polymorphisms. Recently a new nomenclature for ALDH genes has been recommend based on divergent evolution and chromosomal mapping. Two major isoforms designated as cytosolic ALDH1 and mitochondrial ALDH2 can be distinguished by their electrophoretic and kinetic properties as well as by their subcellular localization. Mitochondrial ALDH2 is a major enzyme in the oxidation of acetaldehyde derived from ethanol metabolism. The catalytic deficiency of ALDH2 isozyme is responsible for flushing and other vasomotor symptoms caused by higher acetaldehyde levels after alcohol intake. So far, frequencies of the two alleles of ALDH2 in Mongoloid have been reported in the different population groups. The catalytic deficiency of ALDH2 is caused by a structural point mutation at amino acid position 487, where a substitution of Glu to Lys resulting from a transition of G (C) to A (T) at 1510 nucleotide from the initiation codon has occurred. Individuals deficient in ALDH2 activity refrain from excessive drinking of alcohol due to the aversive reactions, leading to protection against alcoholism. Prevalence of the ALDH2*1 allele is associated with alcoholism, and subsequent studies have confirmed the allelic association with alcoholism in different ethnic groups. The effects of polymorphisms of ADH2 and CYP2E1 remained controversial, even in the same ethnic group. Investigation of mutations for the transacting cis-element in promoter region of the ALDH2 gene will provide important information with respect to regulation of this gene. Transfection assays using the first 600 bp of the upstream nucleotide sequences indicated that a region from -75 to -120 was necessary for the ALDH2 gene expression, and especially NF-Y/CP1 binding site from -92 to -96 (CCAAT box) is important in the expression of the gene. A novel polymorphism due to the nucleotide replacement at -357 G to A was found in all the population groups. Alcoholism is thought to be a multifactorial disease with complex mode of inheritance in addition to psychological and social factors, and many studies of family, adoption and twins concerning alcoholism have revealed that hereditary factor is an important determinant for developing alcoholism. Genetic association studies have contributed to the identification of a number of genetic risk factors for the chronic diseases influenced by genetic disorders and environmental factors.
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PMID:[Classification of alcohol metabolizing enzymes and polymorphisms--specificity in Japanese]. 1139 42

A variety of genetically influenced alcohol-related phenotypes relate to risk for alcohol dependence. In Asians, variation in the alcohol dehydrogenase (ADH2) gene relates to alcohol dependence, alcohol consumption, and reported alcohol-related symptoms, even after controlling for variation in the aldehyde dehydrogenase (ALDH2) gene. The association of ADH2 polymorphisms with alcohol-related behavior, however, has not been well characterized in non-Asians. This study evaluated 84 Ashkenazic Jewish American college students to determine the prevalence of the ADH2*2 allele (0.31). Carriers of ADH2*2 reported significantly fewer drinking days per month. ADH2*2, however, was not related to alcohol use disorders, alcohol-induced flushing and associated symptoms, number of binge drinking episodes in the past 90 days, maximum number of drinks ever consumed, or self-reported levels of response to alcohol. Results suggest that Ashkenazic Jewish Americans with ADH2*2 alleles drink less frequently, which might contribute, in part, to the overall lower rates of alcoholism in this population.
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PMID:ADH2 and alcohol-related phenotypes in Ashkenazic Jewish American college students. 1154 39


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