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)

Inherited variations in alcohol and aldehyde dehydrogenases, the principal enzymes of ethanol metabolism, have been implicated in determining susceptibility to alcoholism and alcohol-related organ damage. An association between an RFLP for the alcohol dehydrogenase-2 (ADH2) gene and alcohol-induced liver damage was demonstrated in a Caucasian population. Genotyping studies revealed an increase in the ADH3(2) allele in patients with alcohol-induced cirrhosis. PCR studies of the ALDH5 gene have demonstrated diverse polymorphism within a short segment of its coding region, with marked inter-racial variation in allele frequencies. In addition, the Caucasian alcohol-induced flushing reaction has been characterised and its relationship with phenotypic polymorphism of ALDH1 examined.
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PMID:Alcohol and acetaldehyde dehydrogenase gene polymorphism and alcoholism. 791 53

Disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, induces a flushing reaction upon the ingestion of ethanol, exerting aversion against alcohol that has been used in the treatment of alcoholism. This unpleasant response has been associated with an accumulation of acetaldehyde, and more recently, with an increase in vascular prostacyclin (PGI2) production. To evaluate the possibility of evoking the flushing reaction with drugs less toxic than disulfiram, we studied the effects of propranolol and dipyridamole on ALDH and PGI2. Acetaldehyde oxidation rate was assessed by gas chromatography in mitochondria from rats treated with these drugs for seven days. Prostacyclin generation was determined in rat aortic rings incubated in Krebs-Ringer with these drugs separately and associated to acetaldehyde, and measured by radioimmunoassay of 6-keto-PGF1 alpha. Propranolol inhibited acetaldehyde oxidation rate whereas dipyridamole did not. Furthermore, propranolol increased blood acetaldehyde levels without affecting ethanol elimination rate. Both drugs stimulated prostacyclin synthesis but only dipyridamole enhanced the stimulatory effect of acetaldehyde on vascular prostacyclin production. These results strongly suggest the possibility of producing a deterrent effect on the consumption of alcohol by using propranolol or dipyridamole. In contrast to disulfiram, these drugs could potentially induce the flushing reaction in humans in the presence of low acetaldehyde concentrations; this new therapeutic approach might have an important clinical and toxicological relevance.
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PMID:Investigations on the ethanol-induced flushing reaction: effects of propranolol and dipyridamole on acetaldehyde and prostacyclin metabolism. 802 34

Influence of genetic polymorphism at the alcohol dehydrogenase2 (ADH2) and aldehyde dehydrogenase2 (ALDH2) loci on ethanol elimination and blood acetaldehyde level was studied in healthy subjects. Polymorphic regions of the ADH2 and ALDH2 genes were amplified for genomic DNA by using the technique of polymerase chain reaction. The ADH2 genotype was determined by digestion with the restriction enzyme MaeIII and the ALDH2 genotype was defined by hybridization with sequence specific oligonucleotide probes. Both loci were typed for unrelated 58 individuals by using the above methods. The gene frequencies of each locus were estimated as follows; 0.31 and 0.69 for ADH2*1 and ADH2*2, respectively, and 0.73 and 0.27 for ALDH2*1 and ALDH2*2, respectively. These values were consistent with the Hardy-Weinberg equilibrium. Pedigree analysis of 6 families with 46 subjects on both loci confirmed Mendelian inheritance. In order to investigate differences in ethanol elimination among ADH2 and ALDH2 genotype groups, 0.4 g/kg body weight of ethanol was administered to 93 subjects whose genotypes of both loci were determined by the above methods and blood ethanol and acetaldehyde levels were measured. None of the subjects homozygous for the ALDH2*1 allele showed facial flushing and any increase in blood acetaldehyde level. All the homozygotes and heterozygotes with the ALDH2*2 allele exhibited facial flushing, and the former showed a marked increase in blood acetaldehyde level and the latter did a mild increase. On the other hand, the influence of the ADH2 genotype on blood acetaldehyde level was not significant. The values of Widmark's beta 60 (mg/ml/hr) and ethanol elimination rate (mg/kg/hr) showed significant differences among the three groups of the ALDH2 genotypes in each group of the three ADH2 genotypes, and in decreasing order of both the values were ALDH 2*1/*1, ALDH2*1/*2, ALDH2*/*2, However, there were no significant differences in the values among the ADH2 genotypes.
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PMID:Genetic polymorphism of alcohol and aldehyde dehydrogenase and the effects on alcohol metabolism. 851 95

Implantation and placentation in the baboon share many morphological features with other primates, as well as having some specific distinctions. The ability to use deturgescence of the sex skin as a method of timing ovulation and the ease with which the uterine lumen can be flushed have been used to examine morphological aspects of blastocyst differentiation and implantation in this species. Preimplantation blastocysts were obtained by non-surgical flushing of the uterus 6-8 days after ovulation, and implantation sites were excised from uteri removed on days 10-16 of gestation. All tissues were prepared for electron microscopy by aldehyde fixation and plastic embedding. Maturation of trophoblast from the compacted morula stage to the expanded blastocyst stage includes increase in numbers of polyribosomes, changes in conformation of mitochondria, and development of an effective endocytic apparatus. An endodermal layer forms beneath the inner cell mass prior to loss of the zona pellucida, and parietal endodermal cells extend beyond the inner cell mass. Azonal blastocysts have regions of syncytial trophoblast adjacent to the inner cell mass, and they may represent adhesion stages of early implantation. In early postimplantation stages, trophoblast replaces the uterine epithelium and processes of syncytial trophoblast invade dilated superficial maternal vessels. In subsequent lacunar stages there is rapid elevation of the developing conceptus above the uterine surface as the lacunae enlarge. Cytotrophoblast rapidly enters maternal vessels, and arterioles are partially or completely occluded by migrating cytotrophoblast. The early access to controlled maternal blood flow apparently allows trophoblastic lacunae to expand superficially as opposed to more extensive endometrial invasion.
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PMID:From blastocyst to placenta: the morphology of implantation in the baboon. 958 46

Acetaldehyde is a widely distributed compound in the human environment and it is also formed in the human body from various endogenous and exogenous sources, exogenous ethanol being the most important one. Many alcohol-associated hypersensitivity reactions, e.g. Oriental flushing reaction, appear to be attributable to acetaldehyde rather than to ethanol itself. The pathogenetic mechanism behind such hypersensitivity reactions has been suggested to be histamine release from mast cells or blood basophils. However, the direct effects of acetaldehyde on mast cells, the main source of histamine in a mammalian body, have not been studied. The aim of the present study was, thus, to evaluate whether physiological concentrations of acetaldehyde could release histamine from purified rat peritoneal mast cells. The effects of ethanol were studied similarly. The results show that acetaldehyde, already at a concentration of 50 microM, significantly increases the release of histamine from mast cells. Ethanol has a similar effect but only at molar concentrations. These results indicate that acetaldehyde may contribute to the development of various hypersensitivity reactions by directly increasing histamine release from mast cells.
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PMID:Acetaldehyde induces histamine release from purified rat peritoneal mast cells. 1002 49

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

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

The role of genetic polymorphisms in modulating xenobiotic metabolism and susceptibility to cancer and other health effects has been suggested in numerous studies. However, risk assessments have generally not used this information to characterize population variability or adjust risks for susceptible subgroups. This paper focuses upon the aldehyde dehydrogenase-2 (ALDH2) system because it exemplifies the pivotal role genetic polymorphisms can play in determining enzyme function and susceptibility. Allelic variants in ALDH2 cause decreased ability to clear acetaldehyde and other aldehyde substrates, with homozygous variants (ALDH2*2/2) having no activity and heterozygotes (ALDH2*1/2) having intermediate activity relative to the predominant wild type (ALDH2*1/1). These polymorphisms are associated with increased buildup of acetaldehyde following ethanol ingestion and increased immediate symptoms (flushing syndrome) and long-term cancer risks. We have used Monte Carlo simulation to characterize the population distribution of ALDH2 allelic variants and inter-individual variability in aldehyde internal dose. The nonfunctional allele is rare in most populations, but is common in Asians such that 40% are heterozygotes and 5% are homozygote variants. The ratio of the 95th or 99th percentiles of the Asian population compared to the median of the U.S. population is 14- to 26-fold, a variability factor that is larger than the default pharmacokinetic uncertainty factor (3.2-fold) commonly used in risk assessment. Approaches are described for using ALDH2 population distributions in physiologically based pharmacokinetic-Monte Carlo refinements of risk assessments for xenobiotics which are metabolized to aldehyde intermediates (e.g., ethanol, toluene, ethylene glycol monomethyl ether).
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PMID:Population distribution of aldehyde dehydrogenase-2 genetic polymorphism: implications for risk assessment. 1247 14

Dental unit water system (DUWS) tubing harbors complex multispecies biofilms that are responsible for high microbial levels at the distal outlet. The aim of this study was to use an established biofilm laboratory model to simulate biofouling of DUWS to evaluate practical, cost-effective, and evidence-based methods of microbial decontamination. Reproducible biofilms were developed in the model over 14 days; decontamination was assessed using total viable counts (TVC) and microscopic-image analysis techniques to view the inner surface of tubing. Flushing did not reduce the biofilm coverage or TVC. Combizyme and ozone did not completely eliminate the viable bacteria (70 and 65% reduction in biofilm TVC, respectively), nor did they remove the biofilm (45 and 57% reduction in biofilm coverage, respectively). Chlorhexidine and Bio2000 (active agent: ethanol and chlorhexidine), Tegodor and Gigasept Rapid (aldehyde based), and Grotanol (hydroxide based) completely eliminated the TVC but did not completely remove biofilm (31, 53 33, 34, and 64.9% reduction of biofilm coverage, respectively). Other products including Grotanol Flussig (phenol based), Betadine (povidone-iodine based), Alpron (chlorite based), and the hydroxide-containing products Sporklenz, Sterilex Ultra, Dialox, Sterilox, Sanosil, Oxigenal, and Grotanat Bohrerbad resulted in a 100% reduction in the biofilm TVC and a >95% reduction in biofilm coverage. The study demonstrated that while many disinfectants achieve a sufficient reduction in TVC they may not necessarily remove unwanted biofilm from the tubing surfaces as tested in this laboratory-controlled biofilm model.
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PMID:Microbiological evaluation of a range of disinfectant products to control mixed-species biofilm contamination in a laboratory model of a dental unit water system. 1278 33

In the history of diabetes, chlorpropamide alcohol flushing test (CPAF) was a big topic in the 1970s to 1980s. Alcohol tolerance after chlorpropamide has prognostic significance, with the intolerant group (CPAF-positive group) being less prone to develop vascular complication than the tolerant group (CPAF-negative group). A mechanism of CPAF has been regarded as the inhibition of aldehyde dehydrogenase 2 (ALDH2) by an N-alkyl-substituted derivative of chlorpropamide, and the expression of these mutations of ALDH2 and alcohol dehydrogenase 2 (ADH2) could determine the alcohol tolerance among the Japanese population. Therefore, we hypothesized that expression of different ALDH2 and ADH2 polymorphisms may induce differences in vascular complications in diabetes and conducted two studies. The first study (study 1) was to determine the association of ALDH2/AHD2 polymorphism with diabetic complications. To know the association of ALDH2/AHD2 polymorphism with diabetic vasculopathy and neuropathy, a total of 158 patients with type 2 diabetes were divided into four groups on the basis of ALDH2 "activity" and ADH2 "superactivity." The frequency of proteinuria and the percentage of proliferative retinopathy among the patients with retinopathy was higher in those with active ALDH2 and superactive ADH2. We speculated that protein kinase C isoforms up-regulated by 4-hydroxynonenal that was detoxified by ALDH2 and ADH2 may account for the long-term development of diabetic nephropathy and severe retinopathy. As for neuropathy, the frequency of symptomatic neuropathy was higher in patients with inactive ALDH2 and usual ADH2. We speculate that increased tissue levels of toxic aldehyde could result from inactive ALDH2 and usual ADH2 expression, which results in the increased level of reactive aldehyde in sensory neuron pathway, thereby causing symptomatic polyneuropathy.
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PMID:ALDH2/ADH2 polymorphism associated with vasculopathy and neuropathy in type 2 diabetes. 1531 96


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