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)

Certain (arylsulfonyl)urea hypoglycemic drugs exemplified by chlorpropamide (CP) are known to interact pharmacologically with alcohol (ethanol) to elicit a chlorpropamide-alcohol flushing (CPAF) reaction that is reminiscent of the disulfiram-ethanol reaction (DER). In the present structure-activity study, designed to elucidate the mechanism of inhibition of aldehyde dehydrogenase (AlDH) by CP, we discovered that the N1-methoxy derivative of CP 2a was a potent inhibitor of AlDH in vivo similar in activity to that of the N1-ethyl derivative 2b. Both 2a and 2b can release n-propyl isocyanate, a known inhibitor of AlDH, nonenzymatically. However, (arylsulfonyl)carbamates that are structurally analogous to 2a were also active inhibitors of AlDH, whereas the corresponding (arylsulfonyl)carbamate analogs of 2b were uniformly without activity. We propose a mechanism of bioactivation of 2a and its analogs that involves initial O-demethylation followed by disproportionation and solvolysis of the intermediate formed to release nitroxyl, the putative inhibitor of AlDH.
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PMID:N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo. 143 74

The relationship between the low Km aldehyde dehydrogenase (ALDH2) phenotype determined by the isoelectric focusing of hair root lysates, facial flushing and alcohol drinking patterns in Japanese (N = 282) was examined. Men who had inactive ALDH2 drank significantly less alcohol than those with active ALDH2. Although the effect was less noticeable, a similar relationship was detected in women. Two types of flushing responses were determined: one due to the inactive ALDH2, the other unrelated to this variant form of the isozyme. A striking difference between these flushing types, in terms of the inhibitory influence over drinking patterns, was noted. Nearly 86% of the subjects who reported always flushing in the face were shown to have inactive ALDH2, whereas infrequent flushing and absence of flushing were associated with active ALDH2. Thus, facial flushing may be used as an indicator of ALDH2 phenotype.
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PMID:The relationship between low Km aldehyde dehydrogenase phenotype and drinking behavior in Japanese. 156 Jun 68

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

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

It has been suggested that raised post-ethanol plasma acetaldehyde levels, from inhibition of aldehyde dehydrogenase, underlie the liability to chlorpropamide, alcohol flushing (CPAF). We tested the hypothesis that acetate formation from acetaldehyde, the reaction catalysed by that enzyme, was also likely to be affected by chlorpropamide (CP) medication. In six healthy non-diabetic 'non-flushers', fasting acetate (Ac +/- s.d. mmol/l) was 0.22 +/- 0.12, and increased by 0.47 +/- 0.14 to peak levels by 30 min after intake of 40 ml dry sherry, which increased plasma ethanol (mmol/l) levels to 10.2 +/- 6.0. After 5 days of CP (250 mg daily), fasting Ac (0.17 +/- 0.05) and increase to peak of Ac and ethanol after 40 ml sherry (0.56 +/- 0.12 and 8.9 +/- 7.2 respectively), were not changed (P n.s.). There was no correlation between Ac and ethanol at any time point. When the studies were repeated in five non-insulin-dependent diabetic 'flushers', both on regular CP medication and after 3 days without CP, there was again no significant difference in fasting and post-ethanol Ac levels between the two studies (fasting 0.18 +/- 0.04 v. 0.17 +/- 0.02, and increase to peak 0.62 +/- 0.13 v. 0.72 +/- 0.18, P n.s.). These results indicate that the conversion of ethanol to acetate is unaffected by CP medication, and furthermore that post-ethanol acetate levels do not predict liability to CPAF.
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PMID:The formation of acetate from ethanol with and without prior chlorpropamide intake in diabetic and non-diabetic subjects. 190 25

The types of isozymes of aldehyde dehydrogenase (ALDH) present in human lymphocytes has been investigated using isoelectric focusing of polyacrylamide gels followed by substrate-specific staining. Lymphocytes obtained from most individuals were found to contain both types I and II ALDH. This group of 'typical' individuals reported that they did not develop marked facial flushing or rapid heart rate after drinking alcohol nor did they develop an erythema to cutaneously applied ethanol. Lymphocytes obtained from 'atypical' individuals who do suffer from alcohol-induced flushing and rapid heart rate and who developed erythema to cutaneous ethanol displayed type II, but not type I, ALDH. Lymphocytes thus appear to be an easily accessible and suitable tissue for determining type I ALDH phenotype.
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PMID:Isoenzymes of aldehyde dehydrogenase in human lymphocytes. 222 Dec 79

Japanese healthy male subjects were divided into two groups, i.e., a normal aldehyde dehydrogenase (ALDH) group with a low Km isozyme of ALDH for acetaldehyde, and a deficient group without it. After intake of 0.4 g/kg alcohol, the deficient group showed high levels of blood acetaldehyde, facial flushing including an increased pulse rate and a fall in diastolic blood pressure, while the normal group did not manifest these changes. In the deficient group, the total kininogen concentration gradually decreased after alcohol intake due to a reduction in low molecular weight kininogen, and plasma prekallikrein remained unchanged. The normal group showed no significant changes in any of these values after alcohol intake. In an in vitro study with pooled plasma, the low concentrations of urinary kallikrein caused a decrease in the low molecular weight kininogen only. These results suggest that kinins released by acetaldehyde-induced activation of glandular kallikreins are associated with the changes in cardiovascular symptoms in deficient group which display flushing after alcohol intake.
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PMID:Possible involvement of kinins in cardiovascular changes after alcohol intake. 232 Jun 52

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

The ethanol patch test, which is considered to be a cutaneous model of flushing, was performed on 311 healthy Japanese (237 adults and 74 children). By comparing the results with aldehyde dehydrogenase (ALDH) phenotype determined by isoelectric focusing from hair roots samples, it was demonstrated that the ethanol patch test is a good indicator of the ALDH phenotype. The usefulness of this test in future studies was discussed.
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PMID:Ethanol patch test--a simple and sensitive method for identifying ALDH phenotype. 265 61

Deficiency of mitochondrial aldehyde dehydrogenase (ALDH I) is an inborn error of metabolism that is responsible for acute alcohol sensitivity (flushing response) observed only in Orientals of Mongoloid origin. Our previous studies using electrophoretic enzyme detection have shown that this deficiency is prevalent among Japanese, Chinese, and other Orientals. We report here the genotyping of ALDH I locus in blood samples of 218 South Korean individuals by means of hybridization analysis with allele-specific oligonucleotide probes and enzymatically amplified human genomic DNA. The results of genotyping are compared with the phenotype analysis in hair roots of the same individuals. Among 62 apparently deficient phenotypes, 58 heterozygote and 4 homozygote deficient genotypes were observed.
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PMID:Genotyping of mitochondrial aldehyde dehydrogenase in blood samples using allele-specific oligonucleotides: comparison with phenotyping in hair roots. 270 32


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