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)

Liver alcohol dehydrogenase (ADH) represents the main enzyme of normal alcohol metabolism. Total activity of this enzyme varies largely due to the occurrence of isoenzymes and of genetic polymorphisms. One genetic variant, called "atypical", is characterized by a higher specific activity. In carriers of this variant enzyme an initially faster rate of ethanol metabolism leads to higher blood acetaldehyde levels. Acetaldehyde, as a toxic intermediary metabolite, causes tachycardia, nausea and flushing of the face. A high frequency for "atypical" ADH is observed in mongolid races and consequently a hypersensitivity to alcohol is often observed in Orientals. Hence, certain genetically determined enzyme patterns may represent an aversive factor with regard to alcohol consumption. In Caucasians the phenotypes with "atypical" ADH are less frequent. However, in individuals with the "atypical" variant regular intake of alcohol may lead to an increased organotoxicity due to acetaldehyde.
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PMID:[Pathobiochemistry of alcoholism]. 45 82

The distribution of the human liver alcohol dehydrogenase, ADH2, and aldehyde dehydrogenase, ALDH2, genotypes in 21 different populations comprising Mongoloids, Caucasoids, and Negroids was determined by hybridization of the amplified genomic DNA with allele-specific oligonucleotide probes. Whereas the frequency of the ADH1(2) allele was found to be relatively high in the Caucasoids, Mexican Mestizos, Brazilian Indios, Swedish Lapps, Papua New Guineans and Negroids, the frequency of the ADH2(2) gene was considerably higher in the Mongoloids and Australian Aborigines. The atypical ALDH2 gene (ALDH2(2)) was found to be extremely rare in Caucasoids, Negroids, Papua New Guineans, Australian Aborigines and Aurocanians (South Chile). In contrast, this mutant gene was found to be widely prevalent among the Mongoloids. Individuals possessing the abnormal ALDH2 gene show alcohol-related sensitivity responses (e.g. facial flushing), have the tendency not to be habitual drinkers, and apparently suffer less from alcoholism and alcohol-related liver disease.
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PMID:Distribution of ADH2 and ALDH2 genotypes in different populations. 173 36

Research into the causes of alcoholism is a relatively recent scientific endeavor. One area of study which could lead to better understanding of the disease is the possibility of a genetic predisposition to alcoholism. Recent work has demonstrated that people have varying complements of enzymes to metabolize alcohol. Current knowledge is examined about the influence of various ethanol metabolizing enzymes on alcohol consumption by Asians and members of other ethnic groups. The two principal enzymes involved in ethanol oxidative metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). ADH is responsible for the metabolism of ethanol to acetaldehyde. ALDH catalyzes the conversion of acetaldehyde to acetate. The different isozymes account for the diversity of alcohol metabolism among individuals. An isozyme of ADH (beta 2 beta 2) is found more frequently in Asians than in whites, and an ALDH isozyme (ALDH2), although present in Asians, often is in an inactive form. The presence of an inactive form of ALDH2 is thought to be responsible for an increase in acetaldehyde levels in the body. Acetaldehyde is considered responsible for the facial flushing reaction often observed among Asians who have consumed alcohol. A dysphoric reaction to alcohol, producing uncomfortable sensations, is believed to be a response to deter further consumption. Although the presence of an inactive ALDH2 isozyme may serve as a deterrent to alcohol consumption, its presence does not fully explain the levels of alcohol consumption by those with the inactive isozyme. Other conditions, such as social pressure, and yet undetermined biological factors, may play a significant role in alcohol consumption.
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PMID:Research on alcohol metabolism among Asians and its implications for understanding causes of alcoholism. 251 95

A much higher incidence of alcohol flushing among Orientals in comparison to Caucasians, i.e., greater than 50% vs 5%-10%, has been attributed to racial differences in alcohol-metabolizing enzymes. A large majority of Orientals are "atypical" in alcohol dehydrogenase-2 locus (ADH2), and their livers exhibit significantly higher ADH activity than the livers of most Caucasians. Approximately 50% of Orientals lack the mitochondrial aldehyde dehydrogenase (ALDH2) activity, and elimination of acetaldehyde might be disturbed. We determined by means of hybridization of genomic DNA samples with allele specific oligonucleotide probes, genotypes of the ADH2 and ALDH2 loci in Japanese alcohol flushers and nonflushers. We found that all individuals with homozygous atypical ALDH2(2)/ALDH2(2) and most of those with heterozygous atypical ALDH1(2)/ALDH2(2) were alcohol flushers, while all subjects with homozygous usual ALDH1(2)/ALDH1(2) were nonflushers. Frequency of the atypical ADH2(2) was found to be higher in alcohol flushers than in nonflushers, but the statistical significance was not established in the sample size examined.
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PMID:Genotype of alcohol dehydrogenase and aldehyde dehydrogenase loci in Japanese alcohol flushers and nonflushers. 271 75

An ethnic predisposition to ethanol-provoked flushing among diverse Mongoloid populations may be the consequence of a delayed oxidation and accumulation of acetaldehyde. Orientals who flush after oral alcohol are more likely to have cutaneous erythema after topical ethanol or propanol, and the cutaneous vascular reaction to primary alcohols is actually provoked by the corresponding aldehyde. The cutaneous reaction to primary alcohols can be totally blocked by pretreatment with 4-methylpyrazole, a potent inhibitor of alcohol dehydrogenase.
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PMID:Cutaneous vascular sensitivity to lower aliphatic alcohols and aldehydes in Orientals. 293 66

The existence of racial differences in alcohol sensitivity between Oriental and Caucasian populations has been well documented. The primary manifestation is a highly visible facial flushing (47-85% in Orientals vs 3-29% in Caucasians) accompanied by other objective and subjective symptoms of discomfort. Even among different Oriental groups, subtle differences in the flushing response and alcohol consumption can exist. North and South American Indian populations differ in phenotypes for alcohol dehydrogenase and aldehyde dehydrogenase, but systematic studies comparing degree of flushing, alcohol elimination rates and blood acetaldehyde levels in these populations are lacking. Although flushing does not automatically 'immunize' an individual against alcohol use, those susceptible tend to consume less alcohol, at least in Orientals. However, the flushing phenomenon cannot be the sole explanation for differences in incidences of alcoholism among different racial groups. Socio-cultural, environmental and genetic factors also have to be considered. An increased incidence of flushing has been found to associate with a familial risk of development of future alcoholism in a Caucasian population. It remains to be determined whether the same is true in Orientals. Most biochemical investigations of the flushing phenomenon have focused on aspects of alcohol metabolism. Based on recent findings, a convincing mechanism is the higher accumulation of acetaldehyde in flushing subjects because they have an unusual, less-active liver aldehyde dehydrogenase isozyme (ALDHI). The possibility that an 'atypical' alcohol dehydrogenase, which is present in 85-90% of Oriental subjects, can contribute to increased blood acetaldehyde levels in flushing subjects cannot be ruled out. Based on results of a small number of pedigree studies which demonstrated familial resemblances in flushing, a pharmacogenetic defect in ALDHI has been proposed to be responsible for flushing. Other possible biochemical mechanisms (e.g. prostaglandins) and genetic defects need to be investigated.
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PMID:Racial differences in alcohol sensitivity. 293 17

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

The metabolism of ethanol and its oxidation product, acetaldehyde, was studied in Japanese volunteers. Subjects who responded by facial flushing and tachycardia were found to accumulate acetaldehyde during ethanol intoxication, in contrast to the near absence of blood acetaldehyde in nonflushing subjects. There were large individual variations in acetaldehyde accumulation observed in the former group, and this accumulation correlated well with the intensity of the physiological responses, but not with rate of ethanol elimination. Oral pretreatment with the alcohol dehydrogenase inhibitor, 4-methylpyrazole, reduced ethanol elimination by 15-25% and strongly suppressed acetaldehyde accumulation. However, here too there was no relation between individual ethanol elimination rate and acetaldehyde accumulation. Furthermore, the change in the blood lactate/pyruvate concentration ratio after ethanol intake was apparently unrelated to the degree of acetaldehyde accumulation. These results, combined with our previous observation of a strong negative correlation between increase in heart rate and activity of cytosolic aldehyde dehydrogenase in erythrocytes, suggest that in flushing Orientals lacking the low-Km aldehyde dehydrogenase isozyme, the alternative cytosolic enzyme is responsible for acetaldehyde oxidation, and its activity probably determines the individual variation of acetaldehyde-mediated physiological responses.
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PMID:Accumulation of acetaldehyde in alcohol-sensitive Japanese: relation to ethanol and acetaldehyde oxidizing capacity. 637 51

4-methylpyrazole (4-MP), an inhibitor of alcohol dehydrogenase, rapidly abolished the accumulation of acetaldehyde following alcohol ingestion both in volunteers pretreated with the Antabuse analog calcium carbimide and in an antabuse-treated alcoholic. 4-MP also attenuated other typical symptoms, including facial flushing and tachycardia, thus suggesting its usefulness in the acute treatment of severe disulfiram-alcohol reactions.
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PMID:The disulfiram (Antabuse)-Alcohol reaction in male alcoholics: its efficient management by 4-methylpyrazole. 703 Jan 8

Individuals with the atypical aldehyde dehydrogenase ALDH2 allele, both homozygous and heterozygous status, are alcohol sensitive and have a markedly reduced risk of developing alcoholic diseases. Genetic abnormalities of the ALDH1 locus are also associated with alcohol flushing. The ALDH3 and ALDHx loci are polymorphic and their variations may affect the development of alcoholic diseases. The variations of alcohol dehydrogenase ADH2 and ADH3 loci have no profound effects on alcohol sensitivity. The newly identified ADH6 gene has hormone response elements, and it may cause the gender difference in alcoholic problems.
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PMID:Genetic polymorphisms of alcohol metabolizing enzymes related to alcohol sensitivity and alcoholic diseases. 769 85


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