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

Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals are inactive ALDH2 phenotype; acute acetaldehyde toxicity has not been evaluated in these populations. We compared the acute acetaldehyde toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2-/-) mice who were administered an intraperitoneal (ip) injection of a single dose of acetaldehyde. This comparison was made based on the LD(50) values of acetaldehyde and the symptoms following the ip injection. Blood acetaldehyde level was measured in the 400 mg/kg dose group. Immediately after administration of acetaldehyde, the mice exhibited hypoactivity and staggering gait. Subsequently, symptoms such as pale skin, prone position, coma, and abnormal deep respiration were observed. In cases of death, dyspnea, wheezing, and hypothermia were observed from 15 to 30 min after the administration. In cases of survival, crouching, bradypnea, flushing and piloerection were observed. Significant latency of symptom recovery was found in the Aldh2+/- mice as compared with the Aldh2+/+ mice; however, no statistical difference was observed in the acetaldehyde LD(50) values. This might be attributable to the absence of a significant difference in the blood acetaldehyde concentrations in both mice during the first 0-15 min following administration; however, acetaldehyde elimination delay was observed in the Aldh2-/- mice as compared with the Aldh2+/+ mice. Acetaldehyde toxicity difference was observed between the Aldh2+/+ and Aldh2-/- mice; however, no difference in acetaldehyde lethality was observed by administration of a single dose of an ip acetaldehyde injection.
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PMID:Aldehyde dehydrogenase 2 activity affects symptoms produced by an intraperitoneal acetaldehyde injection, but not acetaldehyde lethality. 1640 40

Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals have the inactive ALDH2 genotypes (ALDH2*2/*2 and ALDH2*1/*2); acute inhalation toxicity of acetaldehyde has not been evaluated in these populations. We compared the toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2-/-) mice by using the paired acute inhalation test modified from the acute toxic class method (OECD TG433). Blood acetaldehyde level was measured 4 hr after the inhalation. A pair of Aldh2+/+ and Aldh2-/- mice was put into a chamber and was exposed to 5000 ppm of acetaldehyde. At the start of the inhalation, the mice exhibited hypoactivity and closing of the eyes. Subsequently, symptoms such as crouching, bradypnea, and piloerection were observed. Flushing was observed only in the Aldh2+/+ mice. Symptoms such as tears, straggling gait, prone position, pale skin, abnormal deep respiration, dyspnea, and one case of death were observed only in the Aldh2-/- mice. The symptoms did not change 1 hr after inhalation in the Aldh2+/+ mice. In contrast, in the Aldh2-/- mice, the symptoms became more severe until the end of the inhalation. The blood acetaldehyde level in the Aldh2-/- mice was approximately twice that in the Aldh2+/+ mice 4 hr after inhalation. The Aldh2-/- mice evidently showed more severe toxicity as compared with the Aldh2+/+ mice due to acute inhalation of acetaldehyde at a concentration of 5000 ppm. Acetaldehyde toxicity in Aldh2+/+ and Aldh2-/- mice was estimated and classified one class different. Based on this study, acetaldehyde inhalations were inferred to pose a higher risk to ALDH2-inactive human individuals.
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PMID:Paired acute inhalation test reveals that acetaldehyde toxicity is higher in aldehyde dehydrogenase 2 knockout mice than in wild-type mice. 1640 41

Velvetleaf (Abutilon theophrasti Medic), morning glory (Ipomoea purpurea [L.] Roth), and wild mustard (Brassica kaber [D.C.] L. C. Wheeler) seeds exhibited decreased germination with increased planting depth in soil. Flushing the soil for 2 minutes each day with air overcame the inhibition. A sealed in vitro system was used to sample the volatile components produced by weed seeds. Inhibition of seed germination was accompanied by decreased O(2) levels and production of volatile metabolites identified as acetaldehyde, ethanol, and acetone. The effectiveness of these compounds in reducing germination was dependent on O(2) levels.
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PMID:Volatile metabolites controlling germination in buried weed seeds. 1665 59

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

A fully automatic membrane inlet mass spectrometric (MIMS) on-line instrumentation for the analysis of aroma compounds in continuous beer fermentation processes was constructed and tested. The instrumentation includes automatic filtration of the sample stream, flushing of all tubing between samples and pH control. The calibration standards can be measured periodically. The instrumentation has also an extra sample line that can be used for off-line sample collection or it can be connected to another on-line method. Detection limits for ethanol, acetic acid and eight organic beer aroma compounds were from mugl(-1) to low mgl(-1) levels and the standard deviations were less than 3.4%. The method has a good repeatability and linearity in the measurement range. Response times are shorter than or equal to 3min for all compounds except for ethyl caproate, which has a response time of 8min. In beer aroma compound analysis a good agreement between MIMS and static headspace gas chromatographic (HSGC) measurements was found. The effects of different matrix compounds commonly present in the fermentation media on the MIMS response to acetaldehyde, ethyl acetate and ethanol were studied. Addition of yeast did not have any effect on the MIMS response of ethanol or ethyl acetate. Sugars, glucose and xylose, increased the MIMS response of all studied analytes only slightly, whereas salts, ammonium chloride, ammonium nitrate and sodium chloride, increased the MIMS response of all three studied compounds prominently. The system was used for on-line monitoring of continuous beer fermentation with immobilised yeast. The results show that with MIMS it is possible to monitor the changes in the continuous process as well as delays in the two-phase process.
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PMID:On-line monitoring of continuous beer fermentation process using automatic membrane inlet mass spectrometric system. 1896 39

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 East Asian respond with a marked facial flushing and mild to moderate symptoms of intoxication after drinking the amounts of alcohol that has no detectable effect on European. The alcohol sensitivity in Orientals is due to a delayed oxidation of acetaldehyde by an atypical aldehyde dehydrogenase ALDH2487Lys, which is resulted from a structural mutation in gene ALDH2. The atypical ALDH2487Lys allele has been associated with various phenotypic statuses, such as protective against alcohol dependence and the risk of alcohol-related digestive tract cancers. Here, we have examined this SNP, adjacent four non-coding SNPs, and one downstream STRP on ALDH2 gene, in total of 1072 unrelated healthy individuals from 14 Chinese populations and 130 Indian individuals. Five major haplotypes based on five SNPs across the ALDH2 gene 40 kb were found in all East Asian populations. The frequencies of the ancestral haplotype GCCTG and the East Asian special haplotype GCCTA containing the atypical ALDH2487Lys allele were 44.8% and 14.9%, respectively. The frequency of the atypical ALDH2487Lys allele or the East Asian specific haplotype GCCTA is high in Yunnan, South coastal, east coastal of China, and decreased gradually toward inland China, West, Northwest and North China. Combined with demographic history in East Asian, our results showed that the presence of ALDH2487Lys allele in peripheral regions of China might be the results of historical migration events from China to these regions. The origin of ALDH2487Lys could be possibly traced back to ancient Pai-Yuei tribe in South China.
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PMID:Origin and dispersal of atypical aldehyde dehydrogenase ALDH2487Lys. 1939 79

Hydrogen cyanamide is a plant growth regulator used in agriculture to induce bud break in fruit trees. Contact with the skin can result in percutaneous absorption of the substance that inhibits aldehyde dehydrogenase and can induce acetaldehyde syndrome in case of alcohol use. The purpose of this report is to describe two cases of a disulfiram-like syndrome following occupational exposure to hydrogen cyanamide. The first case involved a 59-year-old man who used Dormex, which contains hydrogen cyanamide, without protection after consuming a large amount of alcohol during a meal. In less than 1 hour after the ingestion of alcohol, he developed malaise with flushing of the face, tachycardia, and dyspnea. Manifestations regressed spontaneously under surveillance in the hospital. The second case occurred in a 55-year-old farmer following cutaneous contact with Dormex. Five hours after exposure, he developed disulfiram-like syndrome with flushing, tachycardia, and arterial hypotension after consuming three glasses of wine. The patient recovered spontaneously in 3 hours under surveillance in the hospital. These cases confirm the necessity of avoiding alcohol consumption as recommended in the instructions for use of Dormex and of preventing cutaneous contact during use.
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PMID:Disulfiram-like syndrome after hydrogen cyanamide professional skin exposure: two case reports in France. 1965 87

In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2). This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal (4HNE) and the environmental pollutant acrolein, and also bioactivates nitroglycerin. ALDH2 is best known, however, for its role in ethanol metabolism. The accumulation of acetaldehyde following the consumption of even a single alcoholic beverage leads to the Asian alcohol-induced flushing syndrome in ALDH2*2 homozygotes. The ALDH2*2 allele is semidominant, and heterozygotic individuals show a similar but less severe phenotype. We recently identified a small molecule, Alda-1, that activates wild-type ALDH2 and restores near-wild-type activity to ALDH2*2. The structures of Alda-1 bound to ALDH2 and ALDH2*2 reveal how Alda-1 activates the wild-type enzyme and how it restores the activity of ALDH2*2 by acting as a structural chaperone.
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PMID:Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant. 2006 57


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