Genetic polymorphisms in alcohol metabolizing enzymes as related to sensitivity to alcohol-induced health effects

  • Hirotaka Tanaka
  • Eriko Ikai
  • Yuichi Yamada
Original article

Abstract

Three hundred sixty-seven middle-aged Japanese men were analyzed for genotypes of low Km aldehyde dehydrogenase (ALDH2) and cytochrome P450 2E1, and for the association with alcohol-induced health effects. Homozygotes for the normal ALDH2 gene (NN) and for the mutant gene (MM) and heterozygotes (NM) were found in 60, 6 and 33%, and homozygotes for the c1 gene (c1/1) and c2 gene (c2/2) of P450 2E1, and heterozygotes (c1/2) in 55, 5 and 40% of subjects, respectively. Mean alcohol consumption significantly differed in the three ALDH2 genotypes: 297 g per week in NN, 158 g in NM and 18 g in MM. It was not different in the three P450 2E1 genotypes, but tended to increase from cl/1 to c2/2 in the NN subjects while there was an inverse relationship in the subjects having the M gene. No difference in alcohol-induced health effects was observed in ALDH2 genotypes, but c2/2 genotype showed higher blood pressure and serum uric acid than the other P450 2E1 genotypes in the subjects consuming 200 g or more of alcohol per week. These results suggest an interactive effect of ALDH2 and P450 2E1 genes on alcohol consumption and a higher sensitivity to alcohol-induced health effects in c2/2 genotypes, although larger scale studies are required to confirm these findings.

Keywords

Alcohol ALDH2 Cytochrome P450 2E1 Genotype Health effects 

References

  1. 1).
    Greenfield NJ, Pietruszko R. Two aldehyde dehydrogenases from human liver. Isolation via affinity chromatography and characterizatio of the isozymes. Biochim Biophys Acta 1977;483: 35–45.PubMedGoogle Scholar
  2. 2).
    Harada S, Misawa S, Agarwal DP, Goedde HW. Liver alcohol dehy- drogenase and aldehyde dehydrogenase in the Japanese: Isozyme variation and its possible role in alcohol intoxication. Am J Hum Genet 1980;32: 8–15.PubMedGoogle Scholar
  3. 3).
    Harada S, Agarwal DP, Goedde HW. Isozymes of alcohol dehydrogenase and aldehyde dehydrogenase in Japanese and their role in alcohol sensitivity. Adv Exp Med Biol 1980;39: 31–9.Google Scholar
  4. 4).
    Hayashi S, Watanabe J, Kawajiri K. Genetic polymorphisms in the 5′- flanking region change transcriptional regulation of the human cytochrome P450 II El gene. J Biochem 1991;110: 559–65.PubMedGoogle Scholar
  5. 5).
    Korsten MA, Matsuzaki S, Feinman L, Lieber CS. High blood acetaldehyde levels after ethanol administration. Difference between alcoholic and nonalcoholic subjects. N Engl J Med 1975;292: 386–9.PubMedGoogle Scholar
  6. 6).
    Raskin NH. Alcoholism or acetaldehidism? N Engl J Med 1975;292: 422–3.PubMedGoogle Scholar
  7. 7).
    Lieber CS. Alcohol, protein metabolism and liver injury. Gastroenterol 1980;79: 373–90.Google Scholar
  8. 8).
    Mizoi Y, Ijiri I, Tatsuno Y, et al. Relationship between facial flushing and blood acetaldehyde levels after alcohol intake. Pharmac Biochem Behav 1979;10:303–11.CrossRefGoogle Scholar
  9. 9).
    Zeiner AR, Paredes A, Dix Christensen H. The role of acetaldehyde in mediating reactivity to an acute dose of ethanol among different racial groups. Alcoholism Clin Exp Res 1979;3: 11–8.CrossRefGoogle Scholar
  10. 10).
    Harada S, Agarwal DP, Goedde HW. Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese. Lancet 1981;ii: 982.CrossRefGoogle Scholar
  11. 11).
    Tsutsumi M, Wang JS, Takada A. Hepatic messenger RNA contents of cytochrome P4502E1 in patients with different P4502E1 genotypes. Int Hepatol Commun 1994;2: 135–8.CrossRefGoogle Scholar
  12. 12).
    Watanabe J, Hayashi S, Kawajiri K. Different regulation and expression of the human CYP2E1 gene due to Rsa I polymorphism in the 5′-flanking region. J Biochem 1994;116: 321–6.PubMedGoogle Scholar
  13. 13).
    Enomoto N, Takase S, Takada N, Takada A. Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes. Hepatology 1991;13: 1071–5.PubMedGoogle Scholar
  14. 14).
    Yoshihara H, Sato N, Kamada T, Abe H. Low Km ALDH isozyme and alcoholic liver injury. Pharmac Biochem Behav 1983;18 (Suppl. 1): 425–8.CrossRefGoogle Scholar
  15. 15).
    Shibuya A, Yoshida A. Genotypes of alcohol-metabolizing enzymes in Japanese with alcohol liver disease: A strong association of the usual Caucasian-type aldehyde dehydrogenase gene (ALDH2 1) with the disease. Am J Hum Genet 1988;13: 744–8.Google Scholar
  16. 16).
    Chao YC, Liou SR, Chung YY, et al. Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in chinese patients. Hepatology 1994;19: 360–6.PubMedCrossRefGoogle Scholar
  17. 17).
    Tsutsumi M, Takada A, Wang JS. Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver disease. Gastroenterol 1994;107: 1430–5.Google Scholar
  18. 18).
    Pirmohamed M, Kitteringham NR, Quest LJ, et al. Genetic polymorphism of cytochrome P4502E1 and risk of alcoholic liver disease in Caucasians. Pharmacogenet 1995;5: 351–7.CrossRefGoogle Scholar
  19. 19).
    Maezawa Y, Yamauchi M, Toda G. Association between restriction fragment length polymorphism of the human cytochrome P450 2E1 gene and susceptibility to alcoholic liver cirrhosis. Am J Gatroenterol 1994;89: 561–5.Google Scholar
  20. 20).
    Chao YC, Young TH, Chang WK, Tang HS, Hsu CT. An investigation of whether polymorphisms of cytochrome P4502E1 are genetic markers of susceptibility to alcoholic end-stage organ damage in a Chinese population. Hepatology 1995;22: 1409–14.PubMedGoogle Scholar
  21. 21).
    Carr LG, Hartleroad JY, Liang Y, Mendenhall C, Moritz T, Thomasson H. Polymorphism at the P450 II El locus is not associated with alcoholic liver disease in Caucasian men. Alcoholism Clin Exp Res 1995;19: 182–4.CrossRefGoogle Scholar
  22. 22).
    Enomoto N, Takada A, Date T. 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. Gastroenterol Jpn 1991;26: 440–7.PubMedGoogle Scholar
  23. 23).
    Shibuya A, Yoshida A. Frequency of the atypical aldehyde dehydrogenase-2 gene (ALDH2 2) in Japanese and Caucasians. Am J Hum Genet 1988;43: 741–3.PubMedGoogle Scholar
  24. 24).
    Emery AEH. Elements of Medical Genetics, 2nd ed. Edinburgh, London: E & S Livingstone, 1971.Google Scholar
  25. 25).
    Ishibashi T, Harada S, Tanimura S, Taguchi F. Association among genotypes of aldehyde dehydrogenase 2 and alcohol consumption. Jpn J Alcohol Drug Depend 1994;29: 527–35.Google Scholar
  26. 26).
    Takeshita T, Morimoto K, Mao X, Hashimoto T, Furuyama J. Characterization of the three genotypes of low Km aldegyde dehydrogenase in a Japanese population. Human Genet 1994;94: 217–23.Google Scholar
  27. 27).
    Faller J, Fox IH. Ethanol-induced hyperuricemia. Evidence for increased urate production by activation of adenine nucleotide turnover. N Eng J Med 1982;307: 1598–602.Google Scholar
  28. 28).
    Gordon T, Kannel WB. Drinking and its relation to smoking, BP, blood lipids, and uric acid. Arch Intern Med 1983;143: 1366–74.PubMedCrossRefGoogle Scholar
  29. 29).
    MacMahon S. Alcohol consumption and hypertension. Hypertension 1987;9: 111–21.PubMedGoogle Scholar
  30. 30).
    Ueshima H. Alcohol and hypertension. Jpn J Publ Health 1986;33: 253–7.Google Scholar
  31. 31).
    Ernst N, Fisher M, Smith W, et al. The association of plasma high- density lipoprotein cholesterol with dietary intake and alcohol consumption. The Lipid Research Clinics Program Prevalence Study. Circulation 1880;62 (Suppl. IV): IV 41–52.Google Scholar
  32. 32).
    Anderson KM, Wilson PWF, Garrison RJ, Castelli WP. Longitudinal and secular trends in lipoprotein cholesterol measurements in a general population sample. The Framingham offspring study. Atherosclerosis 1987;68: 59–66.PubMedCrossRefGoogle Scholar
  33. 33).
    Yamada Y, Ishizaki M, Kido T, et al. Elevations of serum angiotensinconverting enzyme and gamma-glutamyl transpeptidase activities in hypertensive drinkers. J Hum Hypertens 1991;5: 183–8.PubMedGoogle Scholar
  34. 34).
    Ikai E, Honda R, Yamada Y. Serum gamma-glutamyl transpeptidase level and blood pressure in nondrinkers: A possible pathogenetic role of fatty liver in obesity-related hypertension. J Hum Hypertens 1994;8: 95–100.PubMedGoogle Scholar
  35. 35).
    Ikai E, Ishizaki M, Suzuki Y, Ishida M, Noborizaka Y, Yamada Y. Association between hepatic steatosis, insulin resistance and hyperinsulinaemia as related to hypertension in alcohol consumers and obese people. J Hum Hypertens 1995;9: 101–5.PubMedGoogle Scholar
  36. 36).
    Facchini F, Chen YDI, Hollenbech CB, et al. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA 1991;266: 3008–11.PubMedCrossRefGoogle Scholar

Copyright information

© Japanese Society of Hygiene 1997

Authors and Affiliations

  • Hirotaka Tanaka
    • 1
  • Eriko Ikai
    • 1
  • Yuichi Yamada
    • 1
  1. 1.Department of HygieneKanazawa Medical UniversityIshikawaJapan

Personalised recommendations