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)

Cephalosporin antibiotics with a 1-methyltetrazole-5-thio side chain have the ability to cause an unpleasant flushing reaction if they are taken some time before the drinking of alcohol. It is proposed that the explanation for this is that the side chain becomes liberated in vivo and oxidized to 5,5'-dithiobis(1-methyltetrazole) or to a mixed disulfide analogue which then inactivates aldehyde dehydrogenase. Support for this proposal is given by the results below concerning the interaction in vitro between the disulfides and sheep liver cytoplasmic aldehyde dehydrogenase. 5,5'-Dithiobis(1-methyltetrazole) has a rapid and pronounced inactivatory effect, very similar in many ways (though not identical) to that of disulfiram, to which it has a structural similarity. (Disulfiram is widely used therapeutically to deter alcoholics from drinking.) 1-Methyl-5-methylthiotetrazole (which is a simple model of the antibiotics) and the free 1-methyltetrazole-5-thiol have no effect on the enzyme in vitro, but methyl 5-(1-methyltetrazolyl) disulfide is a potent inactivator; this also supports the proposed pathway.
Alcohol Clin Exp Res
PMID:The effect of 5,5'-dithiobis(1-methyltetrazole) on cytoplasmic aldehyde dehydrogenase and its implications for cephalosporin-alcohol reactions. 300 85

Chlorpropamide (CP), a sulfonylurea-type oral hypoglycemic agent, is known to provoke a flushing reaction reminiscent of the disulfiram-ethanol reaction in certain individuals. This is manifested in rodents by an increase in blood acetaldehyde levels after ethanol administration. When the sulfonamide N1-nitrogen of CP was substituted with an ethyl group, the product, N1-ethylchlorpropamide, was found to be three times as active as CP in raising ethanol-derived blood acetaldehyde. However, whereas CP lowered fasting blood glucose in rats measured over 6 h, N1-ethylchlorpropamide was devoid of hypoglycemic activity, suggesting that the latter might be potentially useful as an alcohol deterrent agent.
Alcohol Clin Exp Res 1988 Aug
PMID:A nonhypoglycemic chlorpropamide analog that inhibits aldehyde dehydrogenase. 305 78

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

Ethanol-induced flushing (EIF) occurs in up to 80% of Asians and is characterized by facial flushing, tachycardia, and increased cardiac output. Since endogenous opiates and prostaglandins may be mediators of flushing syndromes, we attempted to block EIF in four Asian flushers with single doses of either the opiate antagonist nalmefene, or the prostaglandin synthesis inhibitor indomethacin. Nonflushers (2 Caucasian, 2 Asian) and four Asian flushers were given on separate days water, ethanol (0.4 g/kg p.o.), ethanol plus nalmefene (2 mg i.v.), or ethanol plus indomethacin (50 mg p.o.). Ethanol concentrations of flushers and nonflushers were similar. Mean (+/- SEM) plasma acetaldehyde concentrations of flushers (28.2 +/- 11.8 microM) were significantly greater than nonflushers (1.4 +/- 0.5 microM) following ethanol ingestion (p less than 0.001). Ethanol alone always induced a significant rise in facial skin temperature [mean area under the curve (AUC) = 5142 +/- 648 % delta T x min, p less than 0.01] and of pulse (mean AUC = 1622 +/- 120 bpm x min, p less than 0.001) in flushers compared to water ingestion. A single dose of nalmefene (2 mg i.v.) but not indomethacin (50 mg p.o.), reduced the mean (+/- SEM) ethanol-induced rise in facial skin temperature of flushers by 58 +/- 14% (p less than 0.05) without changing plasma acetaldehyde concentrations. These data are preliminary evidence that the opiate antagonist, nalmefene, blocks some of the vascular manifestations of EIF without altering the elevated plasma concentrations of acetaldehyde.
Alcohol Clin Exp Res 1988 Oct
PMID:Opiate antagonist nalmefene inhibits ethanol-induced flushing in Asians: a preliminary study. 306 20

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

The metabolism of acetaldehyde has received considerable attention in the past years owing to its acute and chronic toxic effects in humans. Aldehyde dehydrogenase (ALDH) catalyzes the oxidation of acetaldehyde in liver and other organs. Two major isozymes of hepatic ALDH (ALDH I or E2 and ALDH II or E1), which differ in their structural and functional properties, have been characterized in humans. The ALDH I with a low Km for acetaldehyde is predominantly of mitochondrial origin and ALDH II which has a relatively higher Km is of cytosolic origin. An inherited deficiency of ALDH I isozyme has been found among Japanese and Chinese which is primarily responsible for producing acute alcohol sensitivity symptoms (flushing response) after drinking mild doses of alcohol. Biochemical, immunochemical and molecular genetics data indicate a structural mutation in the ALDH I isozyme gene responsible for the loss in catalytic activity. Population genetic studies indicate a wide prevalence of this ALDH polymorphism among individuals of Mongoloid race. Flushing response to alcohol shows familial resemblances and preliminary family data from Japan, China and Korea hint to an autosomal codominant inheritance for ALDH I isozyme deficiency. The ALDH polymorphism is apparently responsible for the low incidence of alcoholism in Japanese, Chinese and Koreans. Alcohol-induced sensitivity due to ALDH isozyme deficiency may act as an inhibitory factor against excessive alcohol drinking thereby imparting a protection against alcoholism.
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PMID:Polymorphism of aldehyde dehydrogenase and alcohol sensitivity. 310 30

The so-called Oriental flushing reaction associated with ingestion of small amounts of alcohol was antagonized by combined antihistamine administration. In stage one of the study, the flushing reaction to low doses of alcohol was produced in Orientals. Most subjects experienced a cutaneous flush, an increase in skin temperature, a decrease in blood pressure, an increase in pulse rate and subjective symptoms such as dizziness, sleepiness, anxiety, headache, generalized weakness and nausea. Before the administration of alcohol, one-half of the subjects were given 50 mg of diphenhydramine (H1 receptor antagonist) and 300 mg of cimetidine (H2 receptor antagonist). The second half received placebo tablets. The clearest difference between the antihistamine group and placebo group was in the skin flushing reaction. The antihistamine group showed a significant reduction in the skin flush. The antihistamine also neutralized the systolic hypotension induced by the administration of alcohol. The possible importance of histamine in the expression of sensitivity to alcohol is considered. The relevance to genetic susceptibility for development of alcoholism is discussed.
J Stud Alcohol 1988 Jan
PMID:Antihistamine blockade of alcohol-induced flushing in orientals. 334 71

Multivariate path analysis was used to examine the etiologies of variation and covariation of flushing after alcohol use in nuclear families of Korean, Taiwanese, Japanese and Caucasian ancestries. Phenotypic variances and covariances were partitioned into familial (additive genetic and common family environment) and environmental components. Although alcohol consumption and flushing varied greatly among the different groups, familialities, estimated from components of mother, father and at least one child, were remarkably similar. The familialities for flushing were 0.48 for Japanese, 0.56 for Koreans and 0.35 for Taiwanese; flushing is infrequent in Caucasians and thus was not analyzed. Familialities were lower for consumption, but like flushing, were consistent across ethnic groups (Japanese, 0.27; Koreans, 0.24; Taiwanese, 0.15; Caucasians, 0.28). The genetic correlation between flushing and alcohol consumption was high. Thus, to the extent that flushing influences alcohol consumption, the covariance is most likely genetic.
J Stud Alcohol 1988 May
PMID:Familial transmission of alcohol consumption and the flushing response to alcohol in three Oriental groups. 337 40

In a crossover design experiment, we investigated the elimination kinetics of ethanol and acetaldehyde during the calcium carbimide (CC)-alcohol flush reaction. Ten healthy men swallowed a tablet of calcium carbimide (50 mg) or placebo and about 2 hours later drank 0.25 g/kg ethanol within 5 min. The pulmonary blood concentrations of ethanol and acetaldehyde were estimated indirectly by analysis of end-expired alveolar air. The onset of facial flushing and associated cardiovascular response coincided with the peak concentrations of ethanol and acetaldehyde in blood. The speed of absorption of alcohol was faster in subjects treated with CC. A smaller volume of distribution of ethanol was evident after pretreatment with CC; 0.636 L/kg compared with 0.675 L/kg after placebo. The rate of elimination of ethanol from blood was about 5% slower in subjects given the CC tablet. The disposition kinetics of acetaldehyde were markedly different when aldehyde dehydrogenase (ALDH) was inhibited. The maximum blood-levels of acetaldehyde ranged from 40-242 microM compared with 1.7-6.5 microM in the placebo control experiments. The elimination half-life of acetaldehyde after CC treatment ranged from 18-31 min. Our results do not support a significant role of acetaldehyde in regulating in-vivo metabolism of ethanol in humans.
Alcohol Alcohol Suppl 1987
PMID:Elimination kinetics of ethanol and acetaldehyde in healthy men during the calcium carbimide-alcohol flush reaction. 342 82

Individual differences in response to alcohol have been observed in various ethnic and racial groups. A positive correlation between alcohol sensitivity and elevated blood acetaldehyde level in conjunction with deficiency of an isozyme of aldehyde dehydrogenase (ALDH I) was noted in Japanese subjects given an acute dose of alcohol. Invariably, significantly higher blood acetaldehyde levels were measured in ALDH I-deficient subjects after ethanol loading. The initial flushing in Orientals after alcohol ingestion might be due to their inability to metabolize acetaldehyde quickly and effectively in the absence of the low Km ALDH I isozyme. While Oriental populations of Mongoloid origin showed varying degree of isozyme deficiency, none of the Caucasian or Negroid populations have this isozyme abnormality.
Alcohol Alcohol Suppl 1987
PMID:Aldehyde dehydrogenase polymorphism: molecular basis and phenotypic relationship to alcohol sensitivity. 342 17


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