Summary
The human cytosol alcohol dehydrogenase(ADH) controlled byADH 2 locus is known to be polymorphic. Most Caucasians have the usual enzyme consisting of the usual β1 subunit, while nearly 90% of Orientals have the atypical β2 subunit. At the physiological pH, the cytosol enzyme activity of the atypical liver is much higher than that of the typical liver. It has been suggested that a high frequency of acute alcohol intoxication among Orientals could be related to the rapid accumulation of acetaldehyde due to the atypical ADH. Human liver aldehyde dehydrogenase (ALDH) is also polymorphic. Virtually all Caucasians have two major isozymes,i.e., ALDH-1 and ALDH-2, while about 50% of Orientals have only ALDH-1, missing ALDH-2 component. Since ALDH-2 has high affinity to acetaldehyde, the high incidence of alcohol sensitivity in Orientals could be related to the accumulation of acetaldehyde due to the lack of ALDH-2 component. The usual ADH homodimer α1α1 and the atypical homodimer β2β2 were purified to homogeneity. The specific activity of the atypical enzyme was nearly three orders of magnitude higher than the usual enzyme at the physiological pH. The usual enzyme was rapidly inactivated by iodoacetate, indicating an existence of the “active site cysteine” in the molecule. In contrast, the atypical enzyme was resistant against the iodoacetate inactivation. Peptide mapping analysis revealed that the active site cysteine in the usual α1 subunit is replaced by histidine in the atypical β2 subunit. In the usual β1β1 enzyme, like horse enzyme, the catalytic Zn is expected to link to the sensitive cysteine at position 47, histidine at position 67, and cysteine at presumably position 174, thus making up the active site. In contrast, the active site of the atypical β2β2 enzyme is expected to consist of the catalytic Zn linked to histidine at position 47, histidine at position 67, and cysteine at position around 174. The functional abnormalities of the atypical enzyme can be correlated to its molecular abnormality.
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Borg, S., and Kvande, H. 1981. Control norepinephrine metabolism during alcohol intoxication in addicts and healthy volunteers.Science 213: 1135–1137.
Braggins, T.J., Crow, K.E., and Bott, R.D. 1980. Acetaldehyde and acetate production during ethanol metabolism in perfused rat liver.Adv. Exptl. Med. Biol. 132: 441–449.
Crow, K., Kitson, T.M., MacGibbon, A.K.H., and Bott, R.D. 1974. Intracellular localization and properties of aldehyde dehydrogenase from sheep liver.Biochim. Biophys. Acta 350: 121–128.
Dahl, K.H., and McKinley-McKee, J.S. 1980. Phosphate binding to liver alcohol dehydrogenase studied by the rate of alkylation with affinity labels.Eur. J. Biochem. 103: 47–51.
Davis, V.E., and Walsh, J.J. 1970. Alcohol, amines, and alkaloids: A possible biochemical basis for alcohol addiction.Science 167: 1005–1007.
Dreyer, M., Kühnau, J., and Rüdiger, M.W. 1980. Chlorpropamide-alcohol flushing is not useful for individual genetic counseling of diabetic patients.Clin. Genet. 18: 189–190.
Duritz, G., and Truitt, E.B. 1966. Importance of acetaldehyde in the action of ethanol on brain norepinephrine and 5-hydroxytryptamine.Biochem. Pharmacol. 15: 711–721.
Eckfeld, J.H., and Yonetani, T. 1976. Subcellular localization of the F1 and F2 isozymes of horse liver aldehyde dehydrogenase.Arch. Biochem. Biophys. 175: 717–722.
Edwards, J.A., and Evans, D.A.P. 1967. Ethanol metabolism in subjects possessing typical and atypical liver alcohol dehydrogenase.Clin. Pharmacol. Therapeu. 8: 824–829.
Eklund, H., Nordström, B., Zeppezauer, E., Söderlund, G., Ohlsson, I., Boiwe, T., Söderberg, B-O., Tapia, O. and Brändén, C-I. 1976. Three-dimensional structure of horse liver alcohol dehydrogenase at 2.4 Å resolution.J. Mol. Biol. 102: 27–59.
Eriksson, C.J.P., Marselos, M., and Koivula, T. 1975. The role of cytosolic rat liver aldehyde dehydrogenase in the oxidation of acetaldehyde during ethanol metabolismin vivo.Biochem. J. 152: 709–712.
Ewing, J.A., Rouse, B.A., and Pellizzari, E.D. 1974. Alcohol sensitivity and ethnic background.Am. J. Psychiatr. 131: 206–210.
Fenna, D., Mix, L., Schaefer, O., and Gilbert, J.A.L. 1971. Ethanol metabolism in various racial groups.Can. Med. Assoc. J. 105: 472–475.
Goedde, H.W., Harada, S., and Agarwal, D.P. 1979a. Racial differences in alcohol sensitivity: A new hypothesis.Hum. Genet. 51: 331–334.
Goedde, H.W., Agarwal, D.P., and Harada, S. 1979b. Alcohol metabolizing enzymes: Studies of isozymes in human biopsies and cultured fibroblasts.Clin. Genet. 16: 29–33.
Goedde, H.W., Agarwal, D.P., and Harada, S. 1980. Genetic studies on alcohol-metabolizing enzymes: Detection of isozymes in human hair roots.Enzyme 25: 281–286.
Greenfield, N.J., and Pietruszko, R. 1977. Two aldehyde dehydrogenase from human liver: Isolationvia affinity chromatography and characterization of isozymes.Biochim. Biophys. Acta 483: 35–45.
Harada, S., Agarwal, D.P., and Goedde, H.W. 1979. Aldehyde dehydrogenase in human blood and its possible role in alcohol metabolism. Report 8th Int. Congr. Forensic Blood Grouping. London. pp. 497–502.
Harada, S., Agarwal, D.P., and Goedde, H.W. 1981. Acetaldehyde metabolism and polymorphism of aldehyde dehydrogenase in Japanese.Abstract, 6th Int. Congr. Hum. Genet. 103.
Impraim, C.C., Wang, G., and Yoshida, A. 1982. Structural mutation in a major human aldehyde dehydrogenase gene results in loss of enzyme activity.Am. J. Hum. Genet. in press.
Jörnvall, H. 1970. Horse liver alcohol dehydrogenase. The primary structure of the protein chain of the ethanol-active isozyme.Eur. J. Biochem. 16: 25–40.
Jörnvall, H., and Pietruszko, R. 1972. Structural studies of alcohol dehydrogenase from human liver.Eur. J. Biochem. 25: 283–290.
Kitabatake, N., Sasaki, R., and Chiba, H. 1981. Localization of bovine liver aldehyde dehydrogenase isozymes and their immunological properties.J. Biochem. 89: 1223–1229.
Krebs, H.A. 1966. The role of equilibria in the regulation of metabolism. inCurrent Topics in Cellular Regulation I, Horecker, B.L., and Stadtman, E.R. eds., pp. 45–55. Academic Press, New York.
Leslie, R.D.G., and Pyke, D.A. 1978. Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes.Brit. Med. J. Dec. 2: 1519–1521.
Leslie, R.D.G., and Pyke, D.A. 1979. Sensitivity to enkephalin as a cause of non-insulin dependent diabetes.Lancet Feb.: 341–343.
Li, T-K., Bosron, W.F., Dafeldecker, W.P., Lange, L.G., and Vallee, B.L. 1977. Isolation of π-alcohol dehydrogenase of human liver: Is it a determinant of alcoholism?Proc. Natl. Acad. Sci. USA.74: 4378–4381.
Lieber, C.S., and DeCarli, L.M. 1968. Ethanol oxidation by hepatic microsomes: Adaptive increase after ethanol feeding.Science 162: 197–198.
Lindros, K.O., Vihma, R., and Forsander, O.A. 1972. Utilization and metabolic effect of acetaldehyde and ethanol in the perfused rat liver.Biochem. J. 126: 945–952.
Lundquist, F., and Westerfeld, W.W. 1958. The kinetics of alcohol elimination in man.Acta Pharmacol. Toxicol. 14: 265–289.
Mizoi, Y., Ijiri, I., Tatsuno, Y., Kijima, T., Fujiwara, S., and Adachi, J. 1979. Relationship between facial flushing and blood acetaldehyde levels after alcohol intake.Pharm. Biochem. Behav. 10: 303–311.
Orme-Johnson, W.H., and Ziegler, D.M. 1965. Alcohol mixed function oxidase activity of mammalian liver microsomes.Biochem. Biophys. Res. Commun. 21: 78–82.
Smith, M., Hopkinson, D.A., and Harris, H. 1971. Developmental changes and polymorphism of human liver alcohol dehydrogenase.Am. Hum. Genet. 34: 251–261.
Smith, M., Hopkinson, D.A., and Harris, H. 1972. Alcohol dehydrogenase isozymes in adult human stomach and liver: Evidence for activity of theADH 3 locus.Ann. Hum. Genet. 35: 243–253.
Smith, M., Hopkinson, D.A., and Harris, H. 1973. Studies on the subunit structure and molecular size of the human alcohol dehydrogenase isozymes determined by the different loci,ADH 1,ADH 2, andADH 3.Ann. Hum. Genet. 36: 401–414.
Stamatoyannopoulos, G., Chen, S-H., and Fukui, M. 1975. Liver alcohol dehydrogenase in Japanese: High population frequency of atypical form and its possible role in alcohol sensitivity.Am. J. Hum. Genet. 27: 789–796.
Stowell, A., Hillbom, M., Salaspuro, M., and Lindros, K.O. 1980. Low acetaldehyde levels in blood, breath and cerebrospinal fluid of intoxicated humans as assayed by improved methods.Adv. Exptl. Med. Biol. 132: 635–645.
Teng, Y-S. 1981. Human liver aldehyde dehydrogenase in Chinese and Asiatic Indians: Gene deletion and its possible implication in alcohol metabolism.Biochem. Genet. 19: 107–113.
Truitt, E.B., and Walsh, M.J. 1971. The role of acetaldehyde in the actions of ethanol. InThe Biology of Alcoholism, Vol. 1. Biochemistry, Kissin, B. and Begleiter, H., eds., New York Plenum Pub., New York
Veech, R.L., Guynn, R., and Veloso, D. 1972. The time-course of the effects of ethanol on the redox and phosphorylation states of rat liver.Biochem. J. 127: 387–397.
Von Wartburg, J.P., and Schürch, P.M. 1968. Atypical human liver alcohol dehydrogenase.Ann. New York Acad. Sci. 151: 936–946.
Williamson, D.H., Lund, P., and Krebs, H.A. 1967. The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver.Biochem. J. 103: 514–527.
Williamson, J.R., Scholz, R., Browning, E.T., Thurman, R.G., and Fukami, M.H. 1969. Metabolic effects of ethanol in perfused rat liver.J. Biol. Chem. 244: 5044–5054.
Wilson, J.R., McClearn, G.E., and Johnson, R.C., 1978. Ethnic variation in the use and effects of alcohol.Drug Alcohol Depend. 3: 147–151.
Wolff, P.C. 1972. Ethnic differences in alcohol sensitivity.Science 175: 449–450.
Wolff, P.C. 1973. Vasomotor sensitivity to alcohol in diverse Mongoloid populations.Am. J. Hum. Genet. 25: 193–199.
Yoshida, A., Impraim, C.C., and Huang, I-Y. 1981. Enzymatic and structural differences between usual and atypical human liver alcohol dehydrogenases.J. Biol. Chem. 256: 12430–12436.
Zeiner, A.R., Paredes, A., and Dix Christensen, H. 1979. The role of acetaldehyde in mediating reactivity to an acute dose of ethanol among different racial groups.Clin. Expt. Res. 3: 11–18.
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Yoshida, A. Molecular basis of difference in alcohol metabolism between Orientals and Caucasians. Jap J Human Genet 27, 55–70 (1982). https://doi.org/10.1007/BF01993894
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DOI: https://doi.org/10.1007/BF01993894
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