Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Pharmacokinetic models for ethanol metabolism have contributed to the understanding of ethanol clearance in human beings. However, these models fail to account for ethanol's toxic metabolite, acetaldehyde. Acetaldehyde accumulation leads to signs and symptoms, such as cardiac arrhythmias, nausea, anxiety, and facial flushing. Nevertheless, it is difficult to determine the levels of acetaldehyde in the blood or other tissues because of artifactual formation and other technical issues. Therefore, we have constructed a promising physiologically based pharmacokinetic (PBPK) model, which is an excellent match for existing ethanol and acetaldehyde concentration-time data. The model consists of five compartments that exchange material: stomach, gastrointestinal tract, liver, central fluid, and muscle. All compartments except the liver are modeled as stirred reactors. The liver is modeled as a tubular flow reactor. We derived average enzymatic rate laws for alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH), determined kinetic parameters from the literature, and found best-fit parameters by minimizing the squared error between our profiles and the experimental data. The model's transient output correlates strongly with the experimentally observed results for healthy individuals and for those with reduced ALDH activity caused by a genetic deficiency of the primary acetaldehyde-metabolizing enzyme ALDH2. Furthermore, the model shows that the reverse reaction of acetaldehyde back into ethanol is essential and keeps acetaldehyde levels approximately 10-fold lower than if the reaction were irreversible.
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PMID:A physiologically based model for ethanol and acetaldehyde metabolism in human beings. 1592 32

The genetic polymorphisms of aldehyde dehydrogenase-2 (ALDH2), alcohol dehydrogenase-1B (ADH1B, previously called ADH2), and ADH1C (previously called ADH3) affect the metabolism of alcohol. The inactive ALDH2 encoded by ALDH2*1/*2 and the less-active ADH1B encoded by ADH1B*1/*1 increase the risk of esophageal squamous cell carcinoma in East Asian drinkers. This case-control study involved 96 Japanese men with oral and pharyngeal squamous cell carcinoma (hypopharyngeal cancer in 43 patients and oral/oropharyngeal cancer in 53) and 642 cancer-free Japanese men. The risk of the cancers overall and of hypopharyngeal cancer was increased 3.61- and 10.08-fold, respectively, by ALDH2*1/*2 among moderate-to-heavy drinkers (9+ units/week; one unit = 22 g of ethanol), but the risk of oral/oropharyngeal cancer was not significantly affected by the ALDH2 genotype. The results obtained with a simple alcohol flushing questionnaire were essentially comparable with those obtained by ALDH2 genotyping. Among moderate-to-heavy drinkers, men with the less-active ADH1B*1/*1 had a significantly higher risk of the cancers overall, of hypopharyngeal cancer, and of oral/oropharyngeal cancer (OR = 5.56, 7.21 and 4.24, respectively). In view of the linkage disequilibrium between ADH1B and ADH1C, the ADH1C genotype does not significantly affect cancer risk. The significant independent risk factors for oral and pharyngeal cancer overall among moderate-to-heavy drinkers were inactive ALDH2*1/*2, less-active ADH1B*1/*1, frequent drinking of strong alcohol beverages straight, smoking, and lower intake of green-yellow vegetables. Educating these risks for cancer of the upper aerodigestive tract could be a useful new strategic approach to the prevention of these cancers in Japanese.
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PMID:Genetic polymorphisms of alcohol and aldehyde dehydrogenases, and drinking, smoking and diet in Japanese men with oral and pharyngeal squamous cell carcinoma. 1707 28

Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), less-active alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received follow-up examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV >or= 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked >or=30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions >or=5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index >or= 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations.
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PMID:Risk of squamous cell carcinoma of the upper aerodigestive tract in cancer-free alcoholic Japanese men: an endoscopic follow-up study. 1711 48

Histamine is biogenic amine that exerts the numerous important biological functions. Alcohol affect histamine action because those have common metabolizing enzymes--aldehyde dehydrogenase and aldehyde oxidase. Acetaldehyde can compete with aldehydes derived from histamine metabolism. Increased blood acetaldehyde resulting from abnormalities of alcohol dehydrogenase genotype in the Orientals population can release histamine from mast cells and basophiles, which induces the hypersensitivity reactions (flushing). These reactions may be blocked by antihistamine drugs. H2-receptor antagonists influence on the ethanol metabolism by the inhibition of the activity of alcohol metabolizing enzymes in the stomach and liver. Decreased activity of stomach alcohol dehydrogenase results in an increase in the blood ethanol concentrations, which may impairs the psychomotor skills and exceeds legal limits of driving. There are same evidences that ethanol affects the brain histamine level by the changes in the activity of enzymes involved in the synthesis and metabolism of histamine.
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PMID:[Interactions between ethanol and histamine]. 1808 Jul 1

Alcohol dependence (AD) is a complex disorder with environmental and genetic origins. The role of two genetic variants in ALDH2 and ADH1B in AD risk has been extensively investigated. This study tested for associations between nine polymorphisms in ALDH2 and 41 in the seven ADH genes, and alcohol-related flushing, alcohol use and dependence symptom scores in 4597 Australian twins. The vast majority (4296) had consumed alcohol in the previous year, with 547 meeting DSM-IIIR criteria for AD. There were study-wide significant associations (P<2.3 x 10(-4)) between ADH1B-Arg48His (rs1229984) and flushing and consumption, but only nominally significant associations (P<0.01) with dependence. Individuals carrying the rs1229984 G-allele (48Arg) reported a lower prevalence of flushing after alcohol (P=8.2 x 10(-7)), consumed alcohol on more occasions (P=2.7 x 10(-6)), had a higher maximum number of alcoholic drinks in a single day (P=2.7 x 10(-6)) and a higher overall alcohol consumption (P=8.9 x 10(-8)) in the previous year than those with the less common A-allele (48His). After controlling for rs1229984, an independent association was observed between rs1042026 (ADH1B) and alcohol intake (P=4.7 x 10(-5)) and suggestive associations (P<0.001) between alcohol consumption phenotypes and rs1693482 (ADH1C), rs1230165 (ADH5) and rs3762894 (ADH4). ALDH2 variation was not associated with flushing or alcohol consumption, but was weakly associated with AD measures. These results bridge the gap between DNA sequence variation and alcohol-related behavior, confirming that the ADH1B-Arg48His polymorphism affects both alcohol-related flushing in Europeans and alcohol intake. The absence of study-wide significant effects on AD results from the low P-value required when testing multiple single nucleotide polymorphisms and phenotypes.
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PMID:Associations of ADH and ALDH2 gene variation with self report alcohol reactions, consumption and dependence: an integrated analysis. 1899 23

Liver alcohol dehydrogenase oxidizes ethanol to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase-2 (ALDH2*1). Individuals who carry a low-activity ALDH2 (ALDH2*2) display high blood acetaldehyde levels after ethanol consumption, which leads to dysphoric effects, such as facial flushing, nausea, dizziness, and headache ("Asian alcohol phenotype"), which result in an aversion to alcohol and protection against alcohol abuse and alcoholism. Mimicking this phenotype may reduce alcohol consumption in alcoholics. RNA interference (RNAi) is a cell process in which a short interfering RNA (siRNA) of 21-25 bp guides the degradation of a complementary target mRNA. Thus, siRNAs may be useful in mimicking the Asian phenotype by inhibiting ALDH2 gene expression. We determined the inhibitory effect of three chemically synthesized siRNAs targeted against rat ALDH2 mRNA in human embryonic kidney cells (HEK-293 cell lines) transfected with a plasmid carrying the rat ALDH2 cDNA. Two of the three siRNAs were active, yielding a 65-75% reduction of ALDH2 activity. Based on the most promising siRNA sequence, three short hairpin RNA (shRNA) genes driven by the human U6 RNA promoter were designed and cloned in a plasmid. After transfection of HEK-293 cells, one of the genes was shown to be active, yielding a 50% reduction of ALDH2 activity. This effect is consistent with a 50% reduction in ALDH2 mRNA, whereas neither beta-actin mRNA nor the interferon-inducible transmembrane protein-1 mRNA levels were affected. This study describes chemically synthesized siRNAs and an endogenously synthesized shRNA, which reduce ALDH2 activity and constitute tools that should be of value for further alcohol research.
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PMID:RNA interference against aldehyde dehydrogenase-2: development of tools for alcohol research. 1925 Nov 11

The ethanol in alcoholic beverages and the acetaldehyde associated with alcohol consumption are Group 1 human carcinogens (WHO, International Agency for Research on Cancer). The combination of alcohol consumption, tobacco smoking, the inactive heterozygous aldehyde dehydrogenase-2 genotype (ALDH2*1/*2) and the less-active homozygous alcohol dehydrogenase-1B genotype (ADH1B*1/*1) increases the risk of squamous cell carcinoma (SCC) in the upper aerodigestive tract (UADT) in a multiplicative fashion in East Asians. In addition to being exposed to locally high levels of ethanol, the UADT is exposed to a very high concentration of acetaldehyde from a variety of sources, including that as an ingredient of alcoholic beverages per se and that found in tobacco smoke; acetaldehyde is also produced by salivary microorganisms and mucosal enzymes and is present as blood acetaldehyde. The inefficient degradation of acetaldehyde by weakly expressed ALDH2 in the UADT may be cri! tical to the local accumulation of acetaldehyde, especially in ALDH2*1/*2 carriers. ADH1B*1/*1 carriers tend to experience less intense alcohol flushing and are highly susceptible to heavy drinking and alcoholism. Heavy drinking by persons with the less-active ADH1B*1/*1 leads to longer exposure of the UADT to salivary ethanol and acetaldehyde. The ALDH2*1/*2 genotype is a very strong predictor of synchronous and metachronous multiple SCCs in the UADT. High red cell mean corpuscular volume (MCV), esophageal dysplasia, and melanosis in the UADT, all of which are frequently found in ALDH2*1/*2 drinkers, are useful for identifying high-risk individuals. We invented a simple flushing questionnaire that enables prediction of the ALDH2 phenotype. New health appraisal models that include ALDH2 genotype, the simple flushing questionnaire, or MCV are powerful tools for devising a new strategy for prevention and screening for UADT cancer in East Asians.
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PMID:Alcohol and aldehyde dehydrogenase polymorphisms and a new strategy for prevention and screening for cancer in the upper aerodigestive tract in East Asians. 2118 98

Ingestion of ethanol in the presence of disulfiram may cause a histamine-like reaction due to accumulation of acetaldehyde. These disulfiram-ethanol reactions (DERs) are manifested by hypotension, tachycardia, gastritis, and angioedema. Fomepizole, an inhibitor of alcohol dehydrogenase, may halt progression of this reaction by blocking ethanol metabolism to acetaldehyde. We present 2 cases of disulfiram and alcohol overdose leading to severe reactions unresponsive to fluid resuscitation and treated with a single dose of fomepizole. Case 1: A 20-year-old woman presented after ingestion of vodka and disulfiram. After 11 hours of resuscitation, she had skin flushing, lip swelling, tachycardia, and hypotension. Antihistamines, steroids, and an additional 2 L of normal saline were given without improvement. Fomepizole 15 mg/kg was given with improvement within 1.5 hours, and she was ultimately discharged with no clinical sequelae. Case 2: A 47-year-old woman presented after overdose of vodka and disulfiram. She was tachycardic and hypotensive upon presentation. After administration of 3 L of normal saline, she remained hypotensive and tachycardic. One dose of fomepizole 15 mg/kg was given. Within 1 hour following fomepizole infusion, her blood pressure and heart rate normalized, and she had no further sequelae from her ingestion. Fomepizole may be a safe and effective treatment of severe DERs. We suggest that 1 dose of fomepizole for severe DERs with hypotension unresponsive to fluid resuscitation or for angioedema unresponsive to antihistamines be administered.
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PMID:Fomepizole for severe disulfiram-ethanol reactions. 2120 69

Alcohol use can lead to a cascade of problems such as increased chances of risky behavior and negative health consequences, including alcoholic liver disease and upper gastric and liver cancer. Ethanol is metabolized mainly by 2 major enzymes: alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). Genetic variations of genes encoding the 2 enzymes are very common among East Asians but relatively rare for most other populations. Facial flushing and other physical discomforts after alcohol drinking triggered by accumulation of acetaldehyde through defective genes for ADH and ALDH have been reported. Approximately 40% of East Asians (Chinese, Japanese, and Korean) show facial flushing after drinking alcohol, known as "Asian flush," which is characterized by adverse reactions on alcohol drinking in individuals possessing the fasting metabolizing alleles for ADH, ADH1B*2, and ADH1C*1, and the null allele for ALDH and ALDH2*2. Alcoholism is determined not only by the genetic deficiency but also by behaviors that involve complex interactions between genetic and sociocultural factors. The purpose of this article was to provide nurses with the most current information about genetic and sociocultural influences on alcoholism and alcohol-related health problems specifically for East Asians and implications of this knowledge to nursing practice. The physiological phenomenon of genes and genetics in relation to alcohol metabolism in this special population is emphasized.
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PMID:Asian flushing: genetic and sociocultural factors of alcoholism among East asians. 2527 25

High permeability, high enzyme loading, and strong antifouling ability are the desired features for a biocatalytic membrane to be used in an enzymatic membrane reactor (EMR). To achieve these goals, the membrane sublayer was enriched with laccase by reverse filtration in this case, and the resulting enzyme-loaded sublayer was covered with a dopamine coating. After membrane reversal, the virgin membrane skin layer was facing the feed and the enzymes were entrapped by a polydopamine network in the membrane sublayer. Thus, the membrane sublayer was functionalized as a catalytically active layer. The effects of the original membrane properties (i.e., materials, pore size, and structure), enzyme type (i.e., laccase and alcohol dehydrogenase), and coating conditions (i.e., time and pH) on the resulting biocatalytic membrane permeability, enzyme loading, and activity were investigated. Using a RC10 kDa membrane with sponge-like sublayer to immobilize laccase with dopamine coating, the trade-off between permeability and enzyme loading was broken, and enzyme loading reached 44.5% without any permeability loss. After 85 days of storage and reuse 14 times, more than 80% of the immobilized laccase activity was retained for the membrane with a dopamine coating, while the relative activity was less than 40% without the coating. The resistance to high temperature and acidic/alkaline pH was also improved by the dopamine coating for the immobilized laccase. Moreover, this biocatalytic membrane could resist mild hydrodynamic cleaning (e.g., back-flushing), but the catalytic ability was reduced by chemical cleaning at extreme pH (e.g., 1.5 and 11.5). Since the immobilized enzyme is not directly facing the bulk of EMRs and the substrate can be specifically selected by the separation skin layer, this biocatalytic membrane is promising for cascade catalytic reactions.
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PMID:Functionalization of a membrane sublayer using reverse filtration of enzymes and dopamine coating. 2542 28


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