Population genetic and family studies on aldehyde dehydrogenase deficiency and alcohol sensitivity

Goedde, H. W.; Agarwal, D. P.; Eckey, Rolf; Harada, Shoji

doi:10.1016/0741-8329(85)90099-0

Cited by 89 publications

(74 citation statements)

References 13 publications

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“…This effect was confirmed in other Asian populations by the observation that individuals who were alcoholic (Goedde et al 1983;Harada et al 1983Harada et al , 1985 or who had alcoholic liver disease (Shibuya & Yoshida, 1989) rarely had ALDH2 deficiency or an ALDH2*2 allele. In Japan about 41% of controls were ALDH2 deficient, while only 2-5 % of alcoholics were ALDH2 deficient (Harada et al 1983). In Taiwanese males the frequency of the ALDH2*2 allele was 30 % in a non-alcoholic control group and 6% in alcoholics .…”

Section: Aldehyde Dehydrogenasesupporting

confidence: 57%

“…Family studies suggested that the flush reaction is inherited as a dominant trait (Schwitters et al 1982). The flushing reaction correlates with the accumulation of acetaldehyde (Zeiner et al 1979;Goedde et al 1983;Enomoto et al 1991a). In non-flushers drinking alcohol elicits a small increase in acetaldehyde levels (to 5-10 mM); in flushers the levels are variable, but may exceed 100 mM (Enomoto et al 1991a).…”

Section: Aldehyde Dehydrogenasesmentioning

confidence: 99%

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Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

et al. 2004

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Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH β2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene–environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.

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Section: Aldehyde Dehydrogenasesupporting

confidence: 57%

Section: Aldehyde Dehydrogenasesmentioning

confidence: 99%

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

et al. 2004

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“…This phenotype is usually associated with deficiency in the activity of the mitochondrial aldehyde dehydrogenase (ALDH2)' (1), a tetrameric NAD + -dependent enzyme. This enzyme is responsible for maintaining low concentrations of acetaldehyde in the liver during ethanol oxidation (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…It has a very low Km for acetaldehyde and other short chain aldehydes (-1 pM) and high catalytic efficiency. Activity and gel electrophoretic assays demonstrating the deficiency have been carried out using hair root (1,4,5) and liver biopsy specimens (6) derived from individuals with the flush reaction. To determine the explanation for the deficiency, the enzyme was purified from liver deficient in ALDH2 activity.…”

Section: Introductionmentioning

confidence: 99%

The aldehyde dehydrogenase ALDH22 allele exhibits dominance over ALDH21 in transduced HeLa cells.

et al. 1995

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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 mechanism 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 (AL-DH2E) 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 *-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 *l-expressing cells. Thus, the ALDH2 *2 allele is sufficient to cause ALDH2 deficiency in vitro. (J. Clin. Invest.

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“…Six out of these (20-21 years in age, and 50-61 kg in weight) were of the normal ALDH-1 type and the others (20-22 years in age, and 55-73 kg in weight) were of the ALDH-1 deficient type. The hair root sampling method described by Goedde et al (1983) was used for this identification. Some of the subjects consumed alcohol (up to 10 g/week) and cigarettes (up to 10/day).…”

Section: Introduction Methodsmentioning

confidence: 99%

Effects of H2‐receptor antagonists on ethanol metabolism in Japanese volunteers.

Tanaka

Nakamura

1988

Brit J Clinical Pharma

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The effects of H2‐receptor antagonists (cimetidine, ranitidine, and famotidine) on ethanol metabolism were investigated. Neither in aldehyde dehydrogenase (ALDH)‐1 deficient subjects nor in those with normal ALDH‐1, did the three H2‐receptor antagonists and placebo differ in their effects on the pharmacokinetic parameters of ethanol (i.e. peak time (tmax), metabolic rate (k0), peak serum concentration (Cmax), volume of distribution (V) and area under the concentration‐time curve (AUC). The AUC of acetaldehyde was slightly but significantly (P less than 0.05) larger only after treatment with cimetidine. Cmax and tmax of acetaldehyde were unchanged.

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Population genetic and family studies on aldehyde dehydrogenase deficiency and alcohol sensitivity

Cited by 89 publications

References 13 publications

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

The aldehyde dehydrogenase ALDH22 allele exhibits dominance over ALDH21 in transduced HeLa cells.

Effects of H2‐receptor antagonists on ethanol metabolism in Japanese volunteers.

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Population genetic and family studies on aldehyde dehydrogenase deficiency and alcohol sensitivity

Cited by 89 publications

References 13 publications

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

The aldehyde dehydrogenase ALDH2*2 allele exhibits dominance over ALDH2*1 in transduced HeLa cells.

Effects of H2‐receptor antagonists on ethanol metabolism in Japanese volunteers.

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The aldehyde dehydrogenase ALDH22 allele exhibits dominance over ALDH21 in transduced HeLa cells.