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

A study was performed to verify that the prevalence of alcohol abuse and dependence in Formosan aborigines differs from that of Taiwanese (Chinese Han people), using analysis of aldehyde dehydrogenase (ALDH) isozymes and flush patterns on randomly sampled 70 Atayal, 66 Paiwan, 61 Yami and 94 Taiwanese subjects were studied. The activity of an isomer of ALDH having a low Km (ALDH-I) in hair roots was analysed by isoelectric focusing assay. The subjective experience of flushing response after alcohol ingestion was assessed. Results showed that the rate of ALDH-I deficiency in Taiwanese (51.1%) was significantly higher than in aborigines, i.e., 6.4%, 3.9%, and 0% in Atayal, Paiwan, and Yami subjects, respectively. The percentage occurrence of ALDH-I deficiency and prevalence of alcohol dependence in Taiwanese and aborigines were negatively correlated. The predominant pattern of self-reported flush response after alcohol use among aborigines was of slow onset. The flush response to alcohol ingestion was examined in relation to aldehyde metabolizing enzyme. Since alcohol sensitivity is an important factor in the development and maintenance of the alcohol ingestion habit in humans, our results support the hypothesis that there is a biological basis in the different rates of alcohol abuse and dependence among different ethnic groups.
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PMID:Aldehyde dehydrogenase deficiency, flush patterns and prevalence of alcoholism: an interethnic comparison. 178 Dec 98

The correlation among degrees of alcohol intoxication, facial flushing, blood alcohol concentration (BAC) and blood acetaldehyde level was studied in 117 male alcoholic patients who underwent various tests to assess alcohol influence. Blood samples were collected and alcohol and acetaldehyde levels were determined. BACs ranged from 29 to 577 mg/dl in all patients and from 200 to 299 mg/dl in 48 of them. Fifty-one patients could stand erect (mean BAC [+/- SD] = 189 +/- 80 mg/dl), while 48 showed apparently normal reaction to a walking and turning test (mean BAC = 192 +/- 78 mg/dl). Some of the cases having BACs over 300 mg/dl could still stand and walk while others with BACs under 100 mg/dl already showed psychomotor impairment. Facial flushing was recognized in 75% of the subjects. Acetaldehyde concentrations in 27 patients ranged from 24 to 147 micrograms/dl. Appearance of facial flushing was correlated with relatively high concentrations of blood acetaldehyde. Seven out of 10 healthy volunteers given 1.6 to 2.0 g/kg of alcohol as a control could do nothing but sleep after reaching peak BAC (mean = 232 +/- 21 mg/dl). These findings are taken to indicate a great difference in response to alcohol between alcoholics and healthy men. This study is the first to report the occurrence of facial flushing and raised blood acetaldehyde concentration among Japanese alcoholics.
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PMID:Degrees of alcohol intoxication in 117 hospitalized cases. 194

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

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 cutaneous vasodilation produced by ethanol is exaggerated when acetaldehyde levels are increased after aldehyde dehydrogenase inhibition, producing a flushing reaction, the mechanism of which is unknown. The authors investigated whether ethanol and its metabolites affect the vascular release of prostacyclin, a potent vasodilator, and whether such an effect might be modified by chronic alcohol consumption. Aortic rings from rats fed Chow ad libitum or pair-fed liquid diets containing either ethanol (36% of energy) or isocaloric carbohydrate for 4 to 5 weeks were incubated in Krebs-Ringer bicarbonate supplemented with saturating amounts of arachidonate (10-20 microM) in the presence of ethanol (10-100 mM), acetaldehyde (10-100 microM) or acetate (1.25-5 mM). Prostacyclin was measured by the radioimmunoassay of 6-keto-prostaglandin F1 alpha. Acetaldehyde produced a concentration-dependent stimulation of prostacyclin production both in alcohol-fed and control rats, whereas acetate did not. This effect was associated with increased conversion of arachidonate (either exogenous or released with A23187) and of prostaglandin endoperoxide H2 to prostacyclin. Ethanol did not affect prostacyclin release in control rats, but, in aortas from alcohol-fed animals, 50 mM ethanol did stimulate prostacyclin formation. These effects may contribute to the cardiovascular responses associated with high blood acetaldehyde levels in flushers and with high ethanol levels in alcoholics. In conclusion, acetaldehyde is a potent stimulant of vascular prostacyclin production. This effect is due, at least in part, to enhanced activity of prostacyclin synthase. Ethanol acquires such a stimulatory effect on prostacyclin formation after chronic alcohol consumption.
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PMID:Acute and chronic effects of ethanol and its metabolites on vascular production of prostacyclin in rats. 310 Jul 72

A rise in blood acetaldehyde concentrations following alcohol ingestion was significantly inhibited when healthy nonflushing subjects were administered a clinical dose of pantethine orally. However, similar findings were not observed in flushing (alcohol-sensitive) subjects lacking hepatic low Km aldehyde dehydrogenase (ALDH). The blood ethanol concentrations were not altered by this treatment in either flushing or nonflushing subjects. Acetaldehyde (45 microM) added in vitro to whole blood and plasma obtained 1 hr after pantethine administration disappeared as the incubation continued similarly as with blood and plasma obtained prior to pantethine treatment. Pantethine-related metabolites, such as taurine, pantetheine, coenzyme A, and pantothenate, activated ALDH in vitro. Hepatic acetaldehyde levels following ethanol loading of rats treated with pantethine were much lower than in untreated rats. The pantethine action observed only in nonflushing subjects might be due to an accelerated oxidation of acetaldehyde by the activation of low Km ALDH by pantethine-related metabolites formed in the liver.
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PMID:Lowering of blood acetaldehyde but not ethanol concentrations by pantethine following alcohol ingestion: different effects in flushing and nonflushing subjects. 389 99

Hereditary variations in the handling of a drug (pharmacogenetics) may result in adverse reactions in the skin. Such reactions could result from: (1) an inherited defect in enzymes responsible for drug metabolism (formation or detoxification of potentially toxic metabolites); (2) altered susceptibility of an endogenous metabolic pathway to inhibition by a drug. Increased alcohol-dehydrogenase activity or decreased aldehyde-dehydrogenase activity will predispose an individual to ethanol-induced flushing. Decreased uroporphyrinogen decarboxylase may result in porphyria cutanea tarda. Slow acetylators are more susceptible to developing drug-induced lupus erythematosus. A hypersensitivity syndrome may result if a patient is unable to detoxify the toxic metabolites of a drug such as phenytoin. A pharmacogenetic defect should alert the clinician to the possibility of cross-reactivity with other drugs or potential drug reactions in relatives of the patient.
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PMID:Pharmacogenetics and adverse drug reactions in the skin. 623 48

Chlorpropamide alcohol flushing (CPAF) in non-insulin-dependent diabetics (NIDDs) has been reported to be associated with a lower tendency to develop late complications. The flush was thought to be mediated by enkephalins and prostaglandins. Early studies could not correlate CPAF to increased levels of acetaldehyde in blood and the flush was not regarded as an antabuse-like reaction. In this study, the increase of plasma acetaldehyde during the flush in 13 CPAF positive diabetics was significantly (P less than 0.005) higher than in the 13 CPAF negative diabetics during a CPAF challenge test. The increase of plasma acetaldehyde was reduced to the level of CPAF negative diabetics in three CPAF positive diabetics when they were exposed to alcohol without premedication with chlorpropamide and they did not flush. The normal breakdown of ethanol to acetic acid via acetaldehyde appears to be inhibited by chlorpropamide in the flushers. Acetaldehyde measurement is an objective method to study the chlorpropamide alcohol flush and it appears superior to the measurement of skin temperature.
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PMID:Increase of plasma acetaldehyde. An objective indicator of the chlorpropamide alcohol flush. 726 73

Individuals heterozygous or homozygous for the variant aldehyde dehydrogenase (ALDH2) allele (ALDH2*2), which encodes a protein differing only at residue 487 from the normal protein, have decreased ALDH2 activity in liver extracts and experience cutaneous flushing when they drink alcohol. The mechanisms by which this allele exerts its dominant effect is unknown. To study this effect, the human ALDH2*1 cDNA was cloned and the ALDH2*2 allele was generated by site-directed mutagenesis. These cDNAs were transduced using retroviral vectors into HeLa and CV1 cells, which do not express ALDH2. The normal allele directed synthesis of immunoreactive ALDH2 protein (ALDH2E) with the expected isoelectric point. Extracts of these cells contained increased aldehyde dehydrogenase activity with low Km for the aldehyde substrate. The ALDH2*2 allele directed synthesis of mRNA and immunoreactive protein (ALDH2K), but the protein lacked enzymatic activity. When ALDH2*1-expressing cells were transduced with ALDH2*2 vectors, both mRNAs were expressed and immunoreactive proteins with isoelectric points ranging between those of ALDH2E and ALDH2K were present, indicating that the subunits formed heteromers. ALDH2 activity in these cells was reduced below that of the parental ALDH2*1-expressing cells. Thus, the ALDH2*2 allele is sufficient to cause ALDH2 deficiency in vitro.
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PMID:The aldehyde dehydrogenase ALDH2*2 allele exhibits dominance over ALDH2*1 in transduced HeLa cells. 759 3


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