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PubMed1995

Measuring and reporting the concentration of acetaldehyde in human breath.

Most of the acetaldehyde generated during the metabolism of ethanol becomes tightly bound to endogenous molecules such as haemoglobin, amino acids and certain phospholipids. Free acetaldehyde passes the blood-brain barrier and traces of this toxic metabolite are excreted through the lungs and can be detected in the expired air. The blood/air partition coefficient of acetaldehyde at 34 degrees C, the average temperature of end-expired air, is about 190:1. Because of various problems associated with measuring acetaldehyde in blood samples, several research groups have instead investigated the analysis of acetaldehyde in breath which offers an indirect and alternative approach for clinical and research purposes. However, care is needed when interpreting the results of breath acetaldehyde measurements, because of the possibility of local formation from microflora inhabiting the upper airways and mouth. The concentration of acetaldehyde exhaled in breath after drinking alcohol demonstrates large inter-individual differences depending on various genetic (racial) and environmental factors. Moreover, acetaldehyde is an endogenous metabolite and even without drinking any alcohol the concentrations expelled in breath span from 0.2 to 0.6 nmol/l, with higher levels observed in smokers and abstinent alcoholics. Breath acetaldehyde concentration reached between 5 and 50 nmol/l in European subjects who drank a moderate dose of ethanol (0.4-0.8 g/kg), with the highest values seen in smokers. The concentration of breath acetaldehyde in Japanese subjects after drinking alcohol reached between 200 and 500 nmol/l at the peak. These much higher levels follow because a large proportion of Orientals (40-50%) inherit an inactive form of the low Km mitochondrial isoenzyme of aldehyde dehydrogenase (ALDH2). The highest concentration of breath acetaldehyde were seen in healthy Caucasians who drank a small dose of alcohol (0.25 g/kg) after taking the alcohol-sensitizing drug calcium carbimide, which blocks the action of ALDH isozymes. During the most intense acetaldehyde-flush reaction, breath acetaldehyde reached between 200 and 1300 nmol/l, but even these abnormally high concentrations did not interfere with the analysis of ethanol in breath by means of non-specific infrared analysers currently used in many countries for testing drinking drivers.

Acetaldehyde↗
PubMed1993

Aldehyde dehydrogenase-derived omega-crystallins of squid and octopus. Specialization for lens expression.

omega-Crystallin of the octopus lens is related to aldehyde dehydrogenases (ALDH) of vertebrates (Tomarev, S. I., Zinovieva, R. D., and Piatigorsky, J. (1991) J. Biol. Chem. 266, 24226-24231) and ALDH1/eta-crystallin of elephant shrews (Wistow, G., and Kim, H. (1991) J. Mol. Evol. 32, 262-269). Only very low amounts of omega-crystallin are present in the squid lens. Here, we have cloned omega-crystallin cDNAs of the octopus (Octopus dofleini) and squid (Ommastrephes sloani pacificus) lenses. The deduced amino acid sequences of omega-crystallin from these species are 78% identical to each other, 56-58% identical to cytoplasmic ALDH1 and mitochondrial ALDH2 of vertebrates (which are 66-68% identical to each other), and 40% identical to Escherichia coli and spinach ALDHs. These data are consistent with the idea that the ALDH1/ALDH2 gene duplication in vertebrates occurred after divergence of cephalopods from the line giving rise to vertebrates, but before the separation of squid and octopus. Southern blot hybridization indicated that omega-crystallin is encoded by few genes (possibly just one) in octopus and squid. Northern blot hybridization revealed two bands (2.7 and 9.0 kilobases) of omega-crystallin RNA in the octopus lens and one band (4.2 kilobases) in the squid lens; omega-crystallin RNAs were undetectable in numerous non-lens tissues of octopus and squid, suggesting lens-specific expression of this gene(s). Finally, extracts of the octopus lens had no detectable ALDH activity using different substrates, consistent with omega-crystallin having no enzymatic activity. Taken together, our results suggest that omega-crystallin evolved by duplication of an ancestral gene encoding ALDH and subsequently specialized for refraction in the transparent lens while losing ALDH activity and expression in other tissues.

Aldehyde Dehydrogenase↗
PubMed1994

Genetic polymorphisms of alcohol metabolizing enzymes related to alcohol sensitivity and alcoholic diseases.

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.

Alcoholism↗
PubMed1994

[Blood ethanol levels and the CTP2E1 C2 allele].

The effect of CYP2E1 upon the blood ethanol level was investigated. Blood ethanol concentrations in 2 volunteers whose ADH2, ADH3 and ALDH2 genotypes were identical, were determined after intravenous administrations of 0.15 g/kg of ethanol by gas chromatography. beta 60 (0.28 mg/ml/hr) of the blood ethanol concentration-time curve in one with the CYP2E1 C2 allele was higher than that (0.25 mg/ml/hr) in the other with no C2 allele. It is possible that the C2 allele may correspond to the higher CYP2E1 activity of ethanol metabolism.

Aldehyde Dehydrogenase↗
PubMed1993

[ADH 2, 3 and ALDH 2 gene frequency in Japanese alcoholics].

To elucidate genetic susceptibility to alcoholic liver injury (ALD), polymerase chain reaction (PCR) method assay was developed to detect point mutations in each gene and gene frequency in various liver diseases was studied. It was shown previously that ALDH2(1) gene was more frequently found in patients with ALD (confirmed in this study), probably because they are able to consume too much alcohol (non-flushing type). This study revealed that, in addition to this ALDH heterogeneity, ADH heterogeneity may correlate with the severity of alcoholic liver injury, especially in those was low ADH activity and tend to have severe damage.

Alcohol Dehydrogenase↗
PubMed1995

Candidate genes in alcoholism.

Individual alleles identified by candidate gene analysis have been shown to profoundly influence certain complex behavioral syndromes including vulnerability to alcoholism. The alcohol and aldehyde dehydrogenase polymorphisms, ADH2(2) and ALDH2(2), respectively, are associated with lower vulnerability to alcoholism both in the Orient and also in North America among populations of Taiwanese and Koreans who have immigrated there. Protein structural variants have recently been identified for a series of genes involved in dopamine and serotonin function. Three dopamine receptors exhibit such structural variants, and these include the DRD2 dopamine receptor, which has three relatively rare amino acid substitutions. Structural polymorphisms were detected in five serotonin receptors (5HT1A, 5HT1Db, 5HT2A, 5HT2C, and 5HT7). Association studies between neurotransmitter gene variants and alcoholism are at an earlier stage than with ADH2(2)/ALDH2(2), but results are thus far negative (dopamine DRD4 receptor), equivocal (dopamine DRD2 receptor), or preliminary (tryptophan hydroxylase, 5HT2C and 5HT1Db).

Alcoholism↗
PubMed1994

Alcohol and aldehyde dehydrogenase genotypes, alcoholism and alcohol related disease.

There is evidence for a genetic component to the aetiology of alcohol related problems. An important way of elucidating this is to search for candidate genes which may show an association with these problems. We have examined for associations between ADH and ALDH polymorphisms, and alcoholism and alcohol related diseases. In Asian populations the ALDH2-2 allele appears protective against alcohol abuse and alcoholism, but may favour alcoholic liver disease. The ADH2-2 allele and the ADH3-1 allele seem to play a similar role. These findings deserve confirmation. Improved clinical methodology will be important in future studies.

Alcohol Dehydrogenase↗
PubMed1994

Alcohol dehydrogenase: enzymology and metabolism.

Alcohol dehydrogenase (ADH), the principal enzyme responsible for ethanol oxidation, constitutes a complex family in humans. Based on structural and kinetic features, ADH can be divided into five classes. Low-Km class I beta-ADH and gamma-ADH show genetic polymorphism among racial populations. The allozymes exhibit distinct maximal activities due to single amino acid exchanges at different sites in the coenzyme-binding domain. Class IV mu-ADH also shows ethnic variability: it is detected in the stomach mucosa of Caucasians but not detectable in about 70% of Orientals. Class I, II, IV and V ADH isozymes exhibit tissue-specific distribution. Approximately 50% of Orientals lack the activity of the mitochondrial low-Km aldehyde dehydrogenase (ALDH2). Ethanol- and acetaldehyde-oxidizing activities of the liver, lung, and gastrointestinal tract appear to be correlated with their isozyme patterns of ADH and ALDH and with the allozymes. The frequencies of the alleles ADH(2)2 and ADH(3)1, coding for the high-Vmax beta 2- and gamma 1-ADH respectively, and of the mutant ALDH(2)2 in the Oriental subjects with alcoholism or alcoholic cirrhosis are significantly lower than those in healthy controls. These genotyping results support the current notion that genetic variation in ADH and ALDH may influence drinking behavior and susceptibility for alcoholism and possibly alcohol-induced organ injury by modulating the rate of metabolism of ethanol and acetaldehyde.

Alcohol Dehydrogenase↗
PubMed1995

Ethanol oxidizing enzymes: roles in alcohol metabolism and alcoholic liver disease.

The elucidation of nucleotide and amino acid sequences of the genes and enzymes involved in the metabolism of ethanol has led to the ability to genotype individuals simply and rapidly. Although the different isozymes were once thought to be a likely explanation for between individual differences in alcohol elimination rates, this has not been found to be the case. Other explanations that remain to be investigated include potential regulatory variants in the genes that alter the level of expression of the enzymes, and genetic influences on activity of the malateaspartate shuttle and rates of mitochondrial NADH reoxidation. However, the isozymes encoded by ADH2*2 and ALDH2*2 have been found to influence alcohol drinking behavior or alcoholism substantially. This supports the original premise that the metabolic disposition of ethanol affects individuals' responses to it. The results suggest that any additional variants might also contribute to the spectrum of individual drinking preferences. Among heavy drinkers, the influence of the isozymes on risk of alcoholic liver disease has not been found to be great, suggesting that many other factors, perhaps interacting with the enzyme polymorphisms, are involved in determining susceptibility.

Alcohol Dehydrogenase↗
PubMed1998

[Genetic evaluation of tolerance to alcohol].

Alcohol sensitivity which is genetically controlled changes the risk of alcoholic diseases development in such individuals. There are differences in the allelic frequencies of the ALDH2, ADH2 and ADH3 loci, between alcoholics and nonalcoholics. It was shown that the atypical ALDH2/2 is an alcohol-rejecting gene and the usual ALDH1/2 gene is a major "alcoholic" gene. The kinetic differences of ADH2 isozymes may also affect drinking behavior. In conclusion, genetic polymorphism of the ALDH and ADH genes influence the risk of alcoholism development. It may be possible to control alcoholism by suppression of "alcoholic" genes expression through genomic intervention.

Alcohol Dehydrogenase↗