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At least 19 recordsLinked to original sources
PubMed1991

Genotyping of the aldehyde dehydrogenase 2 (ALDH2) gene using the polymerase chain reaction: evidence for single point mutation in the ALDH2 gene of ALDH2-deficiency.

About half of all Japanese lack the activity of aldehyde dehydrogenase 2 (ALDH2), and suffer a flush after alcohol intake due to the marked elevation of blood acetaldehyde concentration. The cause of ALDH2 deficiency is thought to be a single point mutation in codon 487 of the ALDH2 gene. However, this mutant ALDH2 gene has not yet been cloned and sequenced. We amplified and cloned the exon 12 of the ALDH2 gene using polymerase chain reaction (PCR), and revealed that normal GAA coding glutamic acid is replaced for AAA coding lysine in codon 487 of the mutant ALDH2 gene. Based on this finding, we performed the genotyping of the ALDH2 gene using PCR and allele-specific oligonucleotide probes. The genotypes of 13 subjects with ALDH2-active phenotype were all homozygous for the normal ALDH2 gene (ALDH2(1)), while in 9 subjects with ALDH2-deficient phenotype 2 subjects were homozygous for the mutant ALDH2 gene (ALDH2(2)) and the other 7 subjects were heterozygous for both genes, indicating that the mutant ALDH2 gene is dominant. In 20 normal control subjects, the prevalence of ALDH2(1)/ALDH2(1), ALDH2(1)/ALDH2(2) and ALDH2(2)/ALDH2(2) was 45%, 45% and 10% respectively. On the other hand, in 36 alcoholic liver disease patients, the prevalence of the genotypes was 83%, 17% and 0%. These results confirmed the previous observation that the incidence of ALDH2 deficiency is much lower in alcoholic liver disease patients than in the general population, and suggested that most of the ALDH2 deficient patients with alcoholic liver disease are heterozygous for the normal and mutant ALDH2 genes.

Aldehyde Dehydrogenase↗
PubMed2026

Targeting ALDH2 with Alda-1 to reverse cisplatin resistance in lung adenocarcinoma.

BACKGROUND: Cisplatin resistance remains a major obstacle in lung adenocarcinoma (LUAD) treatment. The role of Aldehyde dehydrogenase 2 (ALDH2), a detoxifying enzyme, in LUAD prognosis and chemoresistance is poorly understood. METHODS: We analyzed ALDH2's prognostic value using clinical cohorts, TCGA, and proteomic data. Cisplatin-resistant cell lines and xenograft models were used to assess the effect of the ALDH2 agonist Alda-1. Molecular mechanisms were investigated via gain/loss-of-function studies. RESULTS: High ALDH2 expression was significantly associated with improved survival in univariate analysis and correlated with a favorable genomic instability profile in LUAD. Pharmacological activation of ALDH2 with Alda-1 restored cisplatin sensitivity in resistant cells and potently enhanced cisplatin's efficacy in vivo. Mechanistically, ALDH2 activation upregulated PKC-ζ, leading to downregulation of the drug efflux pump MDR1. Proteomic analysis further linked low ALDH2 expression to a pro-chemoresistance signature. CONCLUSION: ALDH2 represents a potential prognostic biomarker associated with favorable outcomes in LUAD, particularly in patients receiving chemotherapy. Its activation via Alda-1 overcomes cisplatin resistance by targeting the PKC-ζ/MDR1 axis, presenting a novel therapeutic strategy.

Cisplatin↗
PubMed1988

Frequency of the atypical aldehyde dehydrogenase-2 gene (ALDH2(2)) in Japanese and Caucasians.

All Caucasians have two major aldehyde dehydrogenase isozymes--i.e., the cytosolic ALDH1 and the mitochondrial ALDH2-while approximately 50% of Orientals are atypical and lack the catalytically active ALDH2 in their tissues. The atypical ALDH2(2) gene has a nucleotide base change and produces the defective ALDH2(2) protein, which has a Glu----Lys substitution at the 14th position from the COOH-terminal (Yoshida et al. 1984; Hsu et al. 1985). With the use of a pair of synthetic oligonucleotides-one complementary to the usual ALDH1(2) and the other complementary to the atypical ALDH2(2)-genotypes of 49 unrelated Japanese individuals and 12 Caucasians were determined. The frequency of the atypical ALDH2(2) allele was found to be .35 in the Japanese samples examined. The atypical ALDH2(2) gene was not found in the Caucasians.

Aldehyde Dehydrogenase↗
PubMed1992

Distribution of ADH2 and ALDH2 genotypes in different populations.

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.

Alcohol Dehydrogenase↗
PubMed1990

Developmental changes of aldehyde dehydrogenase isozymes in human livers: mitochondrial ALDH2 isozyme is expressed in fetal livers.

Previous reports suggested that the major cytosolic aldehyde dehydrogenase (ALDH1) was present in fetal and infant livers, but the major mitochondrial isozyme (ALDH2) was absent or severely diminished. Re-examination by means of starch gel electrophoresis followed by enzyme activity staining, and by means of dot blot immuno-hybridization of liver samples with known genotypes of the ALDH2 locus, indicated that both ALDH1 and ALDH2 genes are expressed in fetal and infant livers. In addition, ALDH4 isozyme was also observed. The results imply that a fetus with the 'usual' homozygous ALDH1(2)/ALDH1(2) genotype, but not one with the atypical ALDH1(2)/ALDH2(2) or ALDH2(2)/ALDH2(2), is capable of detoxifying acetaldehyde transferred from the mother.

Aldehyde Dehydrogenase↗
PubMed1987

Direct detection of usual and atypical alleles on the human aldehyde dehydrogenase-2 (ALDH2) locus.

A method for determining human mitochondrial aldehyde dehydrogenase (ALDH2) genotypes was developed. Two 21-base synthetic oligonucleotides, one complementary to the usual ALDH2(1) gene and the other complementary to the atypical ALDH2(2) gene, were used as specific probes for in-gel hybridization analysis of human genomic DNA from either peripheral blood cells or livers. Under appropriate hybridization conditions, these two probes can hybridize to their specific complementary alleles and thus allow the genotyping of the ALDH2 locus.

Aldehyde Dehydrogenase↗
PubMed1992

Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles.

Asian-American men who possess ALDH2*2 alleles and who experience a facial flush after consuming alcohol were carefully matched on drinking history and demographic variables with nonflushing Asian males with only ALDH2*1 alleles. Each man was tested following placebo and a challenge dose of 0.75 ml/kg alcohol. Following alcohol, flushers reported experiencing significantly more positive feelings of intoxication than nonflushers, despite equivalent blood alcohol concentrations. These data suggest that Asians who flush after drinking, particularly those with ALDH2*1/2*2 genotype, have a more intense, although not necessarily a more negative, response to alcohol than comparable nonflushing Asians. This alcohol sensitivity reaction that many Asian flushers experience may contribute to their lower tendency to drink excessively, even though their response to alcohol is not predominantly negative.

Adult↗
PubMed1989

Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant.

Many Orientals lack the mitochondrial aldehyde dehydrogenase (ALDH2) activity responsible for the oxidation of acetaldehyde produced during ethanol metabolism. These individuals suffer the alcohol-flush reaction when they drink alcoholic beverages. The alcohol-flush reaction is the result of excessive acetaldehyde accumulation, and the unpleasant symptoms tend to reduce alcohol consumption. The subunit of this homotetrameric enzyme was sequenced and the abnormality in the inactive enzyme shown to be a substitution of lysine for glutamate at position 487. We have used the polymerase chain reaction to determine the genotypes of 24 livers from Japanese individuals. Correlating genotype with phenotype leads to the conclusion that the allele (ALDH2(2)) encoding the abnormal subunit is dominant.

Aldehyde Dehydrogenase↗
PubMed1991

Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes.

In order to clarify the relationships between acetaldehyde (Ac-CHO) metabolism and low Km (mitochondrial) aldehyde dehydrogenase (ALDH2) genotypes, hepatic ALDH2 activity was determined and serial changes of blood Ac-CHO levels after ethanol administration were analyzed in the individuals homozygous for the normal ALDH2 genes, heterozygous for the normal and mutant ALDH2 genes, and homozygous for the mutant ALDH2 genes. Genomic DNA was extracted from white blood cells and genotyping of ALDH2 was performed using the polymerase chain reaction technique and slot blot hybridization with synthesized oligonucleotide probes specific to the normal and mutant ALDH2 genes. ALDH2 activity was not detectable in the liver in two cases of the mutant homozygote. In four out of eight cases of the heterozygote, hepatic ALDH2 activity was measurable, although the activity was lower compared with that in the normal homozygote. Blood ethanol levels after alcohol administration were not different among the three different ALDH2 genotypes. Blood Ac-CHO levels after drinking of alcohol were significantly higher in the heterozygotes and the mutant homozygotes than in the normal homozygotes. The levels after a moderate amount of ethanol (0.8 g/kg of body weight) in a case of the mutant homozygote were not different from those of the heterozygotes. However, the levels after a small amount of ethanol (0.1 g/kg of body weight) were significantly higher in the mutant homozygotes than in the heterozygotes. These results indicate that hepatic ALDH2 activity is lacking completely, and metabolism of Ac-CHO in the liver is severely impaired in the homozygotes of the mutant ALDH2 genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1985

Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2.

Partial cDNA clones encoding human cytosolic aldehyde dehydrogenase (ALDH1) and mitochondrial aldehyde dehydrogenase (ALDH2) were isolated from a human liver cDNA library constructed in phage lambda gt11. The expression library was screened by using rabbit antibodies against ALDH1 and ALDH2. Positive clones thus obtained were subsequently screened with mixed synthetic oligonucleotides compatible with peptide sequences of ALDH1 and ALDH2. One of the positive clones for ALDH1 contained an insertion of 1.6 kilobase pairs (kbp). The insert encoded 340 amino acid residues and had a 3' noncoding region of 538 bp and a poly(A) segment. The amino acid sequence deduced from the cDNA sequence coincided with the reported amino acid sequence of human ALDH1 [Hempel, J., von Bahr-Lindström, H. & Jörnvall, H. (1984) Eur. J. Biochem. 141, 21-35], except that valine at position 161 in the previous amino acid sequence study was found to be isoleucine in the deduced sequence. Since the amino acid sequence of ALDH2 was unknown, 33 tryptic peptides of human ALDH2 were isolated and sequenced. Based on the amino acid sequence data thus obtained, a mixed oligonucleotide probe was prepared. Two positive clones, lambda ALDH2-21 and lambda ALDH2-36, contained the same insert of 1.2 kbp. Another clone, lambda ALDH2-22, contained an insert of 1.3 kbp. These two inserts contained an overlap region of 0.9 kbp. The combined cDNA contained a sequence that encodes 399 amino acid residues, a chain-termination codon, a 3' untranslated region of 403 bp, and a poly(A) segment. The deduced amino acid sequence was compatible with the amino acid sequences of the tryptic peptides. The degree of homology between human ALDH1 and ALDH2 is 66% for the coding regions of their cDNAs and 69% at the protein level. No significant homology was found in their 3' untranslated regions.

Aldehyde Dehydrogenase↗
PubMed1987

Purification of human liver aldehyde dehydrogenase by high-performance liquid chromatography and identification of isoenzymes by immunoblotting.

Human liver aldehyde dehydrogenase (ALDH) exists in multiple molecular forms. Two different isoenzymes of ALDH have been purified which will oxidize acetaldehyde to acetate. ALDH1 is localized principally in hepatocyte cytosol and exhibits a Km for acetaldehyde of about 0.1 mM at pH 9.5. ALDH2 is mitochondrial in origin and exhibits low Km for acetaldehyde, about 1 microM. We have developed rapid purification procedures for ALDH1 and ALDH2 by use of agarose-AMP affinity chromatography and high-performance anion-exchange liquid chromatography (HPLC). The method takes less time and affords higher yields of the labile ALDH isoenzymes than conventional column chromatography methods. A previously uncharacterized ALDH form has been identified by anion-exchange HPLC which exhibits high Km for acetaldehyde, about 1 mM, and is very labile. Polyclonal antibodies to the purified ALDH1 and ALDH2 isoenzymes have been prepared. As evidenced by immunoblotting of starch gels containing the purified isoenzymes, anti-ALDH1 does not crossreact with ALDH2 and anti-ALDH2 does not crossreact with ALDH1. The anti-ALDH2 antibody identifies the "inactive" variant of ALDH2 in Japanese livers exhibiting the "deficient" ALDH2 phenotype. The sensitivity of detection of ALDH isoenzymes in liver homogenate-supernatants by immunoblotting of starch gels is about 10-fold greater than that by activity staining.

Aldehyde Dehydrogenase↗
PubMed1992

The relationship between low Km aldehyde dehydrogenase phenotype and drinking behavior in Japanese.

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.

Adolescent↗
PubMed1988

Genotypes of alcohol-metabolizing enzymes in Japanese with alcohol liver diseases: a strong association of the usual Caucasian-type aldehyde dehydrogenase gene (ALDH1(2)) with the disease.

Genetic polymorphisms of two major alcohol-metabolizing enzymes-i.e., one of the class I alcohol dehydrogenase isozymes (ADH2) and the mitochondrial aldehyde dehydrogenase (ALDH2)-exist in Japanese and other Orientals but not in Caucasians. Liver ADH activity of about 90% of Orientals is much higher than that of most Caucasians, while approximately 50% of Orientals lack the ALDH2 activity. The genetic differences have been implicated in the high incidence of alcohol sensitivity observed in Orientals. We determined, by means of hybridization of genomic DNA samples with allele-specific synthetic oligonucleotide probes, genotypes of the ADH2 and the ALDH2 loci of Japanese with alcoholic liver diseases and of control subjects. No significant difference between the patient and control groups was found in the ADH2 genotypes. A remarkable genetic difference between the two groups was found in the ALDH2 locus. The frequency of the typical (Caucasian-type) ALDH1(2) gene was found to be .65 and that of the atypical (Oriental type) ALDH2(2) gene was .35 in the controls, while these were .93 and .07, respectively, in the patients. Thus, most (20 of 23) of the Japanese patients were homozygous Caucasian type ALDH1(2)/ALDH1(2), only three were heterozygous ALDH1(2)/ALDH2(2), and none of the patients were homozygous Oriental type ALDH2(2)/ALDH2(2). The results indicate that Japanese with the atypical ALDH2(2) allele are at a much lower risk in developing the alcoholic liver diseases than are those with homozygous, usual (Caucasian-type) ALDH1(2)/ALDH1(2), presumably owing to their sensitivity to alcohol intoxication.

Aldehyde Dehydrogenase↗
PubMed1985

Enzymatic activity of atypical Oriental types of aldehyde dehydrogenases.

Catalytic activity of the atypical Oriental-type aldehyde dehydrogenase-2 (ALDH2) was considered to be null or severely diminished. Recently it was suggested that the atypical ALDH2(2) retained about 30% of the specific activity of the usual ALDH2(1). We reexamined the problem by two-dimensional crossed immunoelectrophoresis. The usual Caucasian livers exhibited two distinctive precipitin peaks, one corresponding to the cytosolic ALDH1 and the other corresponding to the usual mitochondrial ALDH2(1), in both protein stain and enzyme activity stain. In contrast, the atypical Oriental livers exhibited two precipitin peaks in protein stain, but only one peak, corresponding to ALDH1, in enzyme activity stain. These results support the original notion that the atypical ALDH2(2) is enzymatically inactive or far less active than the usual enzyme, refuting the idea of the atypical ALDH2(2) with substantial enzyme activity.

Aldehyde Dehydrogenase↗
PubMedDate not supplied

Molecular abnormality and cDNA cloning of human aldehyde dehydrogenases.

Usual human livers contain two major ALDH isozymes, i.e., cytosolic ALDH1 and mitochondrial ALDH2, while approximately 50% of Orientals are "atypical" and have only the ALDH1 and are missing the ALDH2. Instead, the atypical livers contain an enzymatically inactive but immunologically cross-reactive material (CRM) corresponding to the ALDH2 component. Some Orientals are found to be atypical also in the ALDH1 locus, i.e., they are missing the enzymatically active ALDH1 but contain a large amount of CRM corresponding to the ALDH1 component. cDNA for ALDH1 and that for ALDH2 were cloned and their nucleotide sequences were determined. The amino acid sequences of ALDH1 and ALDH2 were deduced from their cDNA sequences. The molecular abnormality of the inactive ALDH2(2) is found to be the substitution of Glu at the 14th position from the COOH-terminal of the protein by Lys which resulted from G----A transition in the gene.

Aldehyde Dehydrogenase↗
PubMed1992

[ALDH phenotype in eating disorders with and without alcoholism].

Individuals who have inactive low Km aldehyde dehydrogenase (ALDH2) are much less likely to develop alcoholism than those who have active ALDH2. On the other hand, frequent alcoholism has been reported in eating disorder patients. Whether inactive ALDH2 works as an inhibitory factor for alcoholism in these patients is not known. We compared the ALDH2 phenotype in eating disorder patients with and without alcoholism. Among the 25 subjects (4 with anorexia nervosa, 6 with anorexia nervosa and bulimia nervosa, 13 with bulimia nervosa and 2 with eating disorder not otherwise specified according to the DSM-III-R), 13 were alcoholics and 12 were non-alcoholics. Isoelectric focusing of hair roots samples demonstrated that 8% of the alcoholic subjects had the inactive ALDH2, while 58% of the non-alcoholic subjects had this variant form of the isozyme (p < 0.01). The results suggest inactive ALDH2 has a similar inhibitory effect for alcoholism as in eating disorder patients as has been reported in normal populations.

Adult↗
PubMed1988

Localization of cytoplasmic and mitochondrial aldehyde dehydrogenase isozymes in human liver.

Aldehyde dehydrogenase isozymes (ALDH1 or E1 and ALDH2 or E2 according to the classification by Greenfield NJ, Pietruszko R, Biochim Biophys Acta 483:35, 1977) were purified from the human liver to homogeneity by the use of ion exchange chromatography on CM-Sephadex, DEAE-Sephadex, and QAE-Sephadex and affinity chromatography on 5'-AMP Sepharose 4B, and preparative isoelectric focusing agarose electrophoresis. These were injected in rabbits to elicit antibodies against ALDH1 and ALDH2, respectively and their specificities were tested by double immunodiffusion. By gel filtration, the antibodies were separated into F'ab fragments, conjugated with horseradish peroxidase, and served to detect ALDH1 and ALDH2 proteins in normal liver tissue. Immunoelectron microscopy by the preembedding method revealed that the electron-dense materials reacted with anti-ALDH1 antibody were located in the cytoplasm of hepatocytes, mainly around the nuclear membrane, mitochondria, and endoplasmic reticulum; in the mitochondria, however, no staining was demonstrated. In contrast, the reaction with anti-ALDH2 antibody was observed only in the mitochondria. Immunostaining, performed by the enzyme-labeled antibody method demonstrated that in the hepatic lobule, there were no differences of the intensity of ALDH1 antigenicity and that of ALDH2 antigenicity between periportal (zone 1) and pericentral (zone 3) hepatocytes. These results suggest that in the human liver ALDH1 and ALDH2 are distributed equally in the periportal and centrilobular regions.

Aldehyde Dehydrogenase↗