Clinical and Molecular Hepatology (대한간학회지)

The Korean Association for the Study of the Liver (대한간학회)
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Effects of Genetic Polymorphisms of Ethanol-Metabolizing Enzymes on Alcohol Drinking Behaviors

알코올 대사 효소들의 유전적 다형성이 음주 행태 및 간경변증 발생에 미치는 영향

Kee, Joo-Young;Kim, Min-Ok;You, II-Young;Chai, Ji-Young;Hong, Eui-Sil;An, Sung-Chul;Kim, Heon;Park, Seon-Mee;Youn, Sei-Jin;Chae, Hee-Bok
기주영;김민옥;유일영;채지영;홍의실;안성철;김헌;박선미;윤세진;채희복

  • Published : 20030000
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Abstract

Background/Aims: Genetic variations of ethanol-metabolizing enzymes can affect alcohol drinking behavior. The aims of this study were to investigate and compare the distributions of these genetic polymorphisms between a healthy control group and a heavy drinker group which included an alcoholic liver cirrhosis group. Methods: Genotypes of ADH2, ALDH2, CYP2E1, and catalase were identified by polymerase chain reaction and restriction fragment length polymorphism. Genomic DNA was extracted from peripheral leukocytes in 42 healthy controls, 12 heavy drinkers, and 30 alcoholic liver cirrhosis patients. Results: 1) The genotype frequencies of ALDH2 (1*1), ADH2 (1*1), CYP2E1 (c1c1), and catalase1 (TT) were 69%, 55%, 38%, and 12%, respectively in healthy Korean males. 2) There was a significant difference in the distribution of the genetic polymorphism of ALDH2 between the control group and heavy drinker group (12 heavy drinkers and 30 alcoholic liver cirrhosis patients). The genotype frequency of ALDH2 mutant, ALDH2 (1*2) and ALDH2 (2*2) in the heavy drinker group (12%) was significantly lower than that in the control group (30%). 3) We didn't find anyone with ALDH2 homozygote mutant (DD) in the heavy drinker group. 4) There was no significant difference in the distribution of genetic polymorph isms in ADH2, CYF2E1 and catalase1 between the two groups. Conclusions: These results suggest that the absence of ALDH2 mutant genotype is strongly related to heavy drinking behavior. We can not prove, however, any evidence that the polymorphisms of other ethanol-metabolizing enzymes are associated with the determination of alcohol-drinking behavior.

목적: 만성적인 다량의 음주에도 불구하고 알코 올 중독자의 15%만이 알코올성 간경변증에 이르는데, 유전학적인 차이를 포함한 간질환에 대한 개인적인 감수성의 차이가 발병에 중요한 영향을 미칠 것으로 생각된다. 이에 저자들은 정상 대조군, 과음주력이 있으나 간경변증의 증거가 없는 군, 알코올성 간경 변증 환자군 간의 ALDH2, ADH2, CYF2E1, catalase의 네 가지 알코올 대사 효소의 유전자형 빈도 차이가 음주 행태 및 질환 발생을 어느 정도 설명할 수 있는 것인지를 알아보고자 하였다. 대상과 방법: 정상 성인 42명을 정상 대조군 (평균연령 52$\pm$9세)으로, 임상적 흑은 방사선학적으로 알코올성 간경변증이 확실하게 증명된 30명을 알코올성 간경변증군(평균연령 52$\pm$9세)으로, 음주력은 있으나 간질환의 증거가 없는 12명을 과음주자군(평균연령 46$\pm$6세)으로 배정하였다. 환자의 말초혈액 백혈구에서 DNA를 추출한 후, ALDH2, CYF2E1, ADH2, catalase 1 유전자에 대해 PCR을 시행한 후 제한 효소들로 처리하여 제한 분절길이 다형성으로 유전자형을 나누어 각 유전자형의 출현 빈도를 비교하였다. 결과: 1) 본 연구에서 검사한 정상 성인 남자 42예에서 알코올 대사 효소들의 유전자형 빈도는 ADH2는 (1*1), (1*2)가 38%, 36%, ADLH2 (1*1)(야생형), (1*2), (2*2)이 각각 69%, 28%, 2%의 비율로 나타났다. CYF2E1의 경우 c1/c1(야생형) 유전자형이 55%를 차지하였다. catalase1의 경우 TT(야생형)유전자형이 12%를 차지하였다. 2) 정상 대조군과 음주자군(과음주자군파 알코올성 간경변증 환자군의 합)간에 ALDH2 (1*2) 흑은 (2*2) 유전자형 빈도가 유의하게 음주자군에서 낮음을 알 수 있었다. 음주자군 중에서는 ALDH2 효소의 결핍 형 동형접합체 ALDH (2*2)는 한 예도 없었으며 이형접합체만이 5예였으며, 나머지는 모두 야생형 동형접 합체(88%)였다. 3) 정상대조군파 음주자 간에 ADH2, CYF2E1, catalasel 유전자의 유전자형 분포의 차이를 관찰할 수 없었다. 결론: ALDH2 결핍 유전자형 존재는 개인의 음주 행태에 영향을 미치는 인자이나, 음주자군에서 그 결핍 빈도가 낮아 알코올성 간경변증 발병에 미치는 영향을 임상 연구를 통하여 규명하기에는 제한점이 있었다. ADH2, CYF2E1, CAT1 유전자의 경우에는 세 군간에 서로 의미 있는 차이가 없어 질병 발생과, 음주 행태에 있어서 이 유전자들의 역할은 미미할 것으로 생각된다.

Keywords

References

  1. Teli MR, Day CP, Burt AD, Bennett MK, James OF. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet 1995;346:987-990. https://doi.org/10.1016/S0140-6736(95)91685-7
  2. Loft S, Olesen K, Dossing M. Increased susceptibility to liver disease in relation to alcohol consumption in women. Scand J Gastroenterol 1987;22:1251-1256. https://doi.org/10.3109/00365528708996472
  3. Pares A, Caballeria J, Brugueru M, Torres M, Rodes J. Histological course of alcoholic hepatitis: influence of abstinence, sex and extent of hepatic damage. J Hepatol 1986;2:33-42. https://doi.org/10.1016/S0168-8278(86)80006-X
  4. Lieber CS. Liver disease by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improvement treatment. Am J Addict 2001;10 Suppl:29-50.
  5. Day CP, Bassendine MF. Genetic predisposition to alcoholic liver disease. Gut 1992;33:1444-1447. https://doi.org/10.1136/gut.33.11.1444
  6. Lumeng L, Crabb DW. Genetic aspects and risk factors in alcoholism and alcoholic liver disease. Gastroenterol. 1994;107:572-578. https://doi.org/10.1016/0016-5085(94)90185-6
  7. Salway JG. Metabolism at a glance. London: Blackwell scientific publications, 1994;86-87.
  8. Mizoi Y, Ijiri I, Tatsuno Y, et al. Relationship between facial flushing and blood acetaldehyde levels after alcohol intake. Pharmacol Biochem Behav 1979;10:303-311. https://doi.org/10.1016/0091-3057(79)90105-9
  9. Thormasson HR, Edenberg HJ, Crabb DW, et al. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. AmJ Hum Genet 1991;48:677-681.
  10. Goedde HW, Agarwal DP. Polymorphism of aldehyde dehydrogenase and alcohol sensitivity. Enzyme 1987;37:29-44. https://doi.org/10.1159/000469239
  11. Harada S, Zhang S. New strategy for detection of ALDH2 mutant. Alcohol Alcohol Suppl 1993;1A:11-13.
  12. Groppi A, Begueret J, Iron A. Improved methods for genotype determination of human alcohol dehydrogenase (ADH) at ADH2 and ADH3 loci by using polymerase chain reaction directed mutagenesis. Clin Chem 1990;36:1765-1768.
  13. Kawamoto T, Koga M, Murata K, Matsuda S, Kodama Y. Effects of ALDH2, CYP1A1, and CYP2E1 genetic polymorphisms and smoking and drinking habits on toluene metabolism in humans. Toxicol Appl Pharmacol 1995;133:295-304. https://doi.org/10.1006/taap.1995.1154
  14. Ukkola O, Erkkila PH, Savolainen MJ, Kesaniemi YA. Lack of association between polymorphisms of catalase, copper-zinc superoxide dismutase (SOD), extracellular SOD and endothelial nitric oxide synthase genes and macroangiopathy in patients with type 2 diabetes mellitus. J. Intern Med 2001;249:451-459. https://doi.org/10.1046/j.1365-2796.2001.00828.x
  15. 정숙향, 이한주, 윤정환, 이효석, 김정룡. 알코올 대사 효소들의 유전적 다형성이 알코올성 간경변증의 발생에 비치는 영향. 대한간학회지 1998;4:1-11.
  16. 변관수, 권소영, 박상훈 등. 한국인에서 Mitochondrial Aldehyde Dehydrogenase (ALD-H2)의 유전적 결핍이 알코올성 간질환 발생에 미치는 영향. 대한내과학회지 1993;45:328-336.
  17. Enomoto N, Takase S, Yasuhara M, Takada A. Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin Exp Res 1991;15:141-144. https://doi.org/10.1111/j.1530-0277.1991.tb00532.x
  18. Wolff PH. Ethnic differences in alcohol sensitivity. Science 1972;175:449-450. https://doi.org/10.1126/science.175.4020.449
  19. Goedde HW, Harada S, Agarwal DP. Racial differences in alcohol sensitivity: a new hypothesis. Hum Genet 1979;51:331-334.
  20. Enomoto N, Takase S, Takada N, Takada A. Alcoholic liver disease in heterogygotes of mutant and normal aldehyde dehydrogenase-2 genes. Hepatology 1991;13:1071-1075. https://doi.org/10.1002/hep.1840130611
  21. Grant DA. Genetic polymorphism of the alcohol metabolizing enzymes as a basis for alcoholic liver disease. Br. J Addict 1988;83:1255-1259. https://doi.org/10.1111/j.1360-0443.1988.tb03036.x
  22. Peng GS, Wang MF, Chen YC, et al. Involvement of acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase gene in Asians. Pharmacogenetics 1999;9:463-476.
  23. Chen CC, Lu RB, Chen YC, et al. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet 1999;65:795-807. https://doi.org/10.1086/302540
  24. Smith M, Hopkinson DA, Harris H. Developmental changes and polymorphism in human alcohol dehydrogenase. Ann Hum Genet 1971;34:251-271. https://doi.org/10.1111/j.1469-1809.1971.tb00238.x
  25. Yang CS, Tu YY, Koop DR, Coon MJ. Metabolism of nitrosamines by purified rabbit liver cytochrome P-450 isozymes. Cancer Res 1985;45:1140-1145.
  26. 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;22:1409-1414.
  27. Handler JA, Thruman RG. Catalase-dependent ethnol oxidation in perfused rat liver. Requirement for fatty acid-stimulated $H_2O_2$ production by peroxisomes. Eur J Biochem 1988;176;477-484.
  28. Misra UK, Bradford UB, Handler JA, Thruman RG. Chronic ethanol treatment induces $H_2O_2$ production selectively in pericentral regions of the liver lobule. Alcohol Clin Exp Res 1992;16:839-842. https://doi.org/10.1111/j.1530-0277.1992.tb01878.x
  29. Imlay JA, Linn S. DNA damage and oxygen radical toxicity. Science 1988;240:1302-1309. https://doi.org/10.1126/science.3287616
  30. Koechling UM, Amit Z, Negrete JC. Family history of alcoholism and the mediation of alcohol intake by catalase: further evidence for catalase as a marker of the propensity to ingest alcohol. Alcoholism 1995;19:1096-1104. https://doi.org/10.1111/j.1530-0277.1995.tb01586.x
  31. Lee HC, Lee HS, Jung SH, Yi SY, Jung HK, Yoon JH, Kim CY. Association between polymorphism of ethanolmetabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population. J Korean Med Sci 2001;16:745-750. https://doi.org/10.3346/jkms.2001.16.6.745
  32. Morgan MY, Sherlock S. Sex-related differences among 100 patients with alcoholic liver disese. Br J Med 1977;1:939-941. https://doi.org/10.1136/bmj.1.6066.939