H. W. Goedde

Distribution of ADH2 and ALDH2 genotypes in different populations

SummaryThe 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 ADH12allele was found to be relatively high in the Caucasoids, Mexican Mestizos, Brazilian Indios, Swedish Lapps, Papua New Guineans and Negroids, the frequency of the ADH22gene was considerably higher in the Mongoloids and Australian Aborigines. The atypical ALDH2 gene (ALDH22) 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.

Racial differences in alcohol sensitivity: a new hypothesis.

SummaryA hypothesis regarding alcohol sensitivity in Japanese due to a polymorphism of liver aldehyde dehydrogenase (ALDH) is presented. ALDH was found to show two major bands, a faster migrating isozyme with a low Km for acetaldehyde and a slower migrating isozyme with a high Km for acetaldehyde. Out of 40 livers of Japanese, 21 had only the slower migrating isozyme. No such variation was detected in 68 autopsy livers of Germans. Our data suggest that the initial alcohol sensitivity, quite common in individuals of Mongoloid origin, might be due to a delayed oxidation of acetaldehyde rather than its higher than normal production by atypical alcohol dehydrogenase.

Isozyme variations in acetaldehyde dehydrogenase (E.C.1.2.1.3) in human tissues

SummaryNAD-dependent acetaldehyde dehydrogenase (ALDH) of human tissues was investigated by electrophoresis and enzyme assay. ALDH is located mainly in the liver and kidney. The isozymes consist of at least six different components. Five different phenotypes were found in a total of 68 human liver and kidney specimens. It is likely that three isozyme sets are concerned in determining ALDH types. The distribution of various phenotypes of ALDH isozyme sets is presented.

Alcohol metabolizing enzymes: studies of isozymes in human biopsies and cultured fibroblasts.

Rapid and sensitive micromethods for the study of alcohol dehydrogenase and aldehyde dehydrogenase isozymes in skin extracts, cultured fibroblasts and other organs are presented. Possibilities for the application of these techniques to the study of interindividual variations in response to alcohol are discussed. While fibroblasts cultured from a skin biopsy from one Japanese individual revealed a heterodimer (ADH22‐1) of alcohol dehydrogenase, skin extract from another Japanese showed a homodimer (ADH22‐2). Up to four isozyme sets for aldehyde dehydrogenase (ALDH) were detected in various human organs and at least three sets were found in skin and fibroblast extracts. Our preliminary data on liver, stomach, and skin indicate that ALDH is polymorphic and several loci are concerned in the determination of these isozyme sets.

Aldehyde Dehydrogenase Polymorphism and Alcohol Metabolism in Alcoholics

Significant differences in the incidence of aldehyde dehydrogenase isozyme I deficiency were observed between healthy controls and alcoholics in Japan. Only about 5% of alcoholics were found deficient as compared to about 42% in the normal healthy population. Blood acetaldehyde level after alcohol drinking was also found significantly higher in deficient subjects than in individuals without deficiency. Among alcoholics, deficient subjects showed relatively less elevated blood acetaldehyde levels. When two districts in Japan were compared, per capita alcohol consumption correlated with the frequency of isozyme deficiency. Higher percentage of aldehyde dehydrogenase isozyme deficiency was associated with lower per capita alcohol consumption. Thus, individuals deficient in aldehyde dehydrogenase isozyme may consume less alcohol.

Cytogenetic effects of acetaldehyde in lymphocytes of Germans and Japanese: SCE, clastogenic activity, and cell cycle delay

SummaryAcetaldehyde, the first metabolite of ethanol oxidation, caused a dose-dependent linear increase in the induction of sister chromatid exchanges in lymphocytes from both Germans and Japanese. Japanese, possessing only aldehyde dehydrogenase II isozyme (ALDH I deficient phenotype) and showing adverse effects after alcohol ingestion, did not differ in SCE rates from Germans and Japanese possessing isozymes I and II. At acetaldehyde concentrations above 360 μM, a significant chromosome breaking effect and a definite delay in cell cycle events, as evaluated by the BdUrd labeling technique, was registered in all individuals. Pyridoxal 5′-phosphate showed no protective effect against acetaldehyde-induced SCE formation in our system. A 24-h extension of the normal culture period revealed significantly higher rates of SCE at acetaldehyde doses above 360 μM.

Human breast cancer: frequent p53 allele loss and protein overexpression

A sample of 114 primary breast tumors and corresponding constitutional DNA were tested for loss of heterozygosity (LOH) of the YNZ22 and p53 genes, both located in the 17p13 region. Loss of the p53 allele was found in 28 of 44 primary breast carcinomas (64%). In contrast LOH in only 26 of 61 tumors (43%) was detected with the variable number of tandem repeats (VNTR) probe YNZ22 mapping at 17p13.3 close to the p53 locus at 17p13.1. Among 19 tumors informative for both probes allele loss at 17p13.3 never occurred without p53 involvement. These data suggest, that p53 is the target of 17p13 allelic deletions in human breast cancer. Immunohistochemistry showed overexpression of the p53 protein in 25 of 50 cases (50%) presumably reflecting activating point mutations. Overexpression was not correlated with allele loss but seemed to be closely related to the presence of point mutations in this study. No homozygous deletions or rearrangements of the p53 gene were detected. This would argue for an important role of heterozygous p53 mutations in human breast cancer.

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

Population genetic studies on the prevalence of aldehyde dehydrogenase isozyme I (ALDH I) deficiency in various Caucasian, Oriental, African, and American Indian subjects were carried out using hair roots as peripheral source of the enzyme activity. While a very high percentage of Orientals with Mongoloid origin were found deficient in ALDH I activity, no deficiency was detected in Caucasian and African populations. Native American Indians showed a relatively low incidence of ALDH I deficiency. A genetic model based on the phenotype determination using antisera against purified human liver ALDH I is proposed. Pedigree analysis of Japanese families suggests an autosomal codominant mode of inheritance.

Distribution of alpha-1-antitrypsin and haptoglobin phenotypes in bladder cancer patients

Frequencies of the alpha 1-antitrypsin (Pi) alleles and haptoglobin phenotypes have been determined in a series of 264 North-German patients with bladder cancer. Compared to a healthy control population, we found a statistically significant decrease of Hp 2-2 phenotype in the patient series. A significant increase of the serum Pi Z allele, as previously shown for patient groups with certain other tumours, could also be confirmed for bladder cancer. Furthermore, a distinct association between a lowered M 3 allele and bladder carcinoma was observed.

Incidence of Specific Anosmia in Northern Germany

Thresholds for the perception of 6 primary odorants were tested in a sample of 153 unrelated healthy individuals including 101 males and 52 females. Using some special precautions and directions for preparing aqueous solutions of primary odorants, screening for specific anosmia was found to be a practicable method with reliable results. The observed perception thresholds showed a bimodal distribution. Individuals with higher values probably are specific anosmics. Relatively lower frequencies of anosmia observed in this sample, as compared to reported values in Caucasians of the USA, are probably due to genetic differences. The pheromone character of some odorants and their possible genetic relevance is discussed.