CYP2E1屬於人體內酒精代謝途徑中微粒體乙醇氧化系統(MEOS)的酵素，在酒精代謝過程扮演重要角色，CYP2E1基因多型性影響個體對酒精的感受性，在基因5’ 側端區RsaI/PstI限制酶多型性，其突變型的c2對偶基因會增加基因轉錄活性、mRNA及蛋白質表現量。
酒精經CYP2E1轉變為乙醛過程中，產生大量活性氧，引發氧化壓力增加並且產生大量的自由基，引起細胞膜脂質過氧化作用，造成酒精性肝病與器官組織傷害，近年流行病學研究顯示，台灣地區原住民飲酒盛行率較非原住民高，Bosron 等人認為飲酒的行為受到環境與基因的影響，此種差異亦受族群影響甚大，本實驗藉由高飲酒率的原住民，探討飲酒習性與CYP2E1 Rsa I/Pst I基因多型性對血液生化指標之影響，實驗結果發現，飲酒的男性原住民在血壓、三酸甘油脂、高密度脂蛋白、尿酸及AST的數值皆高於未飲酒者，而在總膽固醇、低密度脂蛋白與肌酸酐的數值皆低於未飲酒者；而飲酒的女性原住民在血壓、高密度脂蛋白、尿酸、肌酸酐及AST的數值皆高於未飲酒者，而在總膽固醇、低密度脂蛋白的數值皆低於未飲酒者，但是飲酒的男性原住民及有無飲酒的女性原住民其CYP2E1基因型對生化指標之作用均未達到統計差異，未飲酒的男性原住民其CYP2E1基因型為c1/c2 + c2/c2與c1/c1相較，有較高的WHR (0.93±0.05 vs. 0.90±0.06，p = 0.035)及ALT (30.0±22.0 vs. 21.5±11.0，p = 0.012)，
p值< 0.05具統計意義。本研究的結論為男性原住民CYP2E1基因型帶有c2對偶基因者，可能與肥胖及肝功能異常有關。

The microsomal ethanol oxidizing system (MEOS) is involved in metabolism of alcohol in the liver, the major component of MEOS is cytochrome P4502E1 (CYP2E1). CYP2E1 gene polymorphisms that alter its functions may be associated with alcohol susceptibility in individual. A RsaI/PstI restriction fragment length polymorphism (RFLP) has been reported in the 5’-flanking region of CYP2E1 gene. The rare mutant allele (c2 allele) that lacks the Rsa I restriction site, but can cut with Pst I has been found to be associated with higher transcriptional activity, mRNA expression, protein levels and enzyme activity than the commom wild type-c1 allele. CYP2E1-dependent oxidative stress on the pathogenesis of alcohol-induced liver injury. The recent epidemiological studies have point out that there are a high prevalence of alcohol consumption in aborigines of Southern taiwan. Dr.Bosron presented an drinks wine the behavior receives the environment and the genetic factor influence, this kind of difference also receives the racial influence to be really big. This study focus on the aborigines with high alcohol drinks rate to examine the possible effect on drinks habit and gene polymorphism of CYP2E1 RsaI/PstI to blood biochemicial index. The experimental result found that male aborigines drinker in blood pressure, triglyceride, HDL cholesterol, uric acid and AST value more than male aborigines non-drinker. However the values are in T.cholesterol, LDL cholesterol, creatinine less than non-drinker. The female aborigines drinker in blood pressure, HDL cholesterol, uric acid, creatinine and AST value more than female aborigines non-drinker. However the values are in T.cholesterol and LDL cholesterol less than non-drinker. Nevertheless, male aborigines drinker and female aborigines non-drinker did not achieved diversity of statistical in function of CYP2E1 gene polymorphism to biochemical index. Male aborigines non-drinkers have c1/c2+c2/c2 in CYP2E1 gene polymorphism compare to c1/c1 also have
higher WHR (0.93±0.05 vs. 0.90±0.06, p = 0.035) and ALT (30.0±22.0
IU/L vs. 21.5±11.0 IU/L , p = 0.012). To summary, male aborigines who have c2 allele in CYP2E1 gene polymorphism may relate to obese and Liver dysfuction.

目 錄

中文摘要 2
英文摘要 4
緒論 6
材料與方法 15
結果 24
討論 28
參考文獻 32
圖表 37
中英文對照50
附錄 51

Agarwal DP. (2001). Genetic polymorphisms of alcohol metabolizing enzymes.
Pathologie Biologie (Paris). 49: 703-709.

Angulo P, Lindor KD. (2001). Insulin resistance and mitochondrial abnormalities in
NASH: a cool look into a burning issue. Gastroenterology. 120: 1281-1285.

Aviram M, Kent UM and Hollenberg PF. (1999). Microsomal cytochromes P450
catalyze the oxidation of low density lipoprotein. Atherosclerosis. 143: 253-260.

Bartsch H and Montesano R. (1984). Relevance of nitrosamines to human cancer.
Carcinogenesis (Lond). 5: 1381-1393

Bosron WF and Li TK. (1986). Genetic polymorphism of human liver alcohol and
aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism. Hepatology. 6: 502-510.

Caballeria J. (2003). Current concepts in alcohol metabolism. Annals of Hepatology.
2: 60-68.

Carr LG, Yi IS, Li TK and Yin SJ. (1996). Cytochrome P4502E1 genotypes,
alcoholism, and alcoholic cirrhosis in Han Chinese and Atayal Natives of Taiwan. Alcoholism,Clinical and Experimental research. 20: 43-46.

Chen WJ, Loh EW, Hsu YP and Cheng AT. (1997). Alcohol dehydrogenase and
aldehyde dehydrogenase genotypes and alcoholism among Taiwanese aborigines.
Society of Biological Psychiatry. 41: 703-709.

Cushman WC. (2001). Alcohol consumption and hypertension. Jounal of Clinical
Hypertesions (Greenwich). 3: 166-170.

Dilger K, Metzler J, Bode JC and Klotz U. (1997). CYP2E1 activity in patients with
alcoholic liver disease. Jounal of Hepatology. 27: 1009-1014.

Dupont I, Lucas D, Clot P, Menez C and Albano E. (1998). Cytochrome P4502E1
inducibility and hydroxyethyl radical formation among alcoholics. Journal of
Hepatology . 28: 564-571.

Guengerichi FP, Kim DH and Iwasaki, M. (1991). Role of human cytochrome
P4502E1 in the oxidation of many low molecular weight cancer suspects.
Chemical Research in Toxicology. 4: 168-179.

Hashimoto Y, Futamura A, Nakarai H and Nakahara K. (2001). Relationship between
response of gamma-glutamyl transpeptidase to alcohol drinking and risk factors
for coronary heart disease. Atherosclerosis. 15: 465-470.

Hayashi S, Watanabe J and Kawajiri K. (1991). Genetic polymorphisms in the
5'-flanking region change transcriptional regulation of the human cytochrome
P4502E1 gene. The Journal of Biological Chemistry(Tokyo). 110: 559-65.

Heath AC, Bucholz KK, Madden PA, Dinwiddie SH, Slutske WS, Bierut LJ, Statham
DJ, Dunne MP, Whitfield JB and Martin NG. (1997). Genetic and environmental
contributions to alcohol dependence risk in a national twin sample: consistency
of findings in women and men. Psychological Medicine. 27: 1381-1384.

Hines LM, Stampfer MJ, Ma J, Gaziano JM, Ridker PM, Hankinson SE, Sacks F,
Rimm EB and Hunter DJ. (2001). Genetic variation in alcohol dehydrogenase
and the beneficial effect of moderate alcohol consumption on myocardial
infarction. The New England Journal of Medicine. 55: 344-549.

Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR,
Rodriguez-Iturbe B, Herrera-Acosta J and Mazzali M. (2003). Is there a
pathogenetic role for uric acid in hypertension and cardiovascular and renal
disease. Hypertension. 41: 1183-90.

Konishi T, Calvillo M, Leng AS, Feng J, Lee T, Lee H, Smith JL, Sial SH, Berman
N, French S, Eysselein V, Lin KM and Wan YJ. (2003). The ADH3*2 and
CYP2E1 c2 alleles increase the risk of alcoholism in Mexican American men.
Experimental and Molecular Pathology. 74: 183-189.

Kunitoh S, Imaoka S, Hiroi T, Yabusaki Y, Monna T and Funae Y. (1997).
Acetaldehyde as well as ethanol is metabolized by human CYP2E1. The Journal
of Pharmacology and Experimental Therapeutics. 280: 527-532.

Lieber CS. (1991). Hepatic, metabolic and toxic effects of ethanol: update.
Alcoholism,Clinical and Experimental Research. 15: 573-592.

Lieber CS. (2004). CYP2E1: from ASH to NASH. Hepatology Research. 28: 1-11.

Lieber CS, Leo MA, Mak KM, Xu Y, Cao Q, Ren C, Ponomarenko A and DeCarli
LM. (2004). Model of nonalcoholic steatohepatitis. The American Jounal of
Clinical Nutrition. 79: 502-509.

Lin HZ, Yang SQ, Zeldin G and Diehl AM. (1998). Chronic ethanol consumption
induces the production of tumor necrosis factor-alpha and related cytokines in
liver and adipose tissue. Alcoholism, Clinical and Experimental research. 22:
231-237.

Liu S, Park JY, Schantz SP, Stern JC and Lazarus P. (2001). Elucidation of CYP2E1
5' regulatory RsaI/Pstl allelic variants and their role in risk for oral cancer. Oral
Oncology. 37: 437-445.

Mukamal KJ, Jadhav PP, D'Agostino RB, Massaro JM, Mittleman MA, Lipinska I,
Sutherland PA, Matheney T, Levy D, Wilson PW, Ellison RC, Silbershatz H,
Muller JE and Tofler GH. (2001). Alcohol consumption and hemostatic factors:
analysis of the Framingham Offspring cohort. Circulation. 104: 1367-1373.

Nakanishi N, Yoshida H, Nakamura K, Suzuki K and Tatara K. (2001). Predictors for
development of hyperuricemia: an 8-year longitudinal study in middle-aged
Japanese men. Metabolism. 50: 621-626.

Nieto N, Friedman SL, Greenwel P and Cederbaum AI. (1999). CYP2E1-mediated
oxidative stress induces collagen type I expression in rat hepatic stellate cells.
Hepatology. 30: 987-996.

Okubo Y, Miyamoto T, Suwazono Y, Kobayashi E and Nogawa K. (2001). Alcohol
consumption and blood pressure in Japanese men. Alcohol. 23: 149-156.

O'Shea D, Davis SN, Kim RB and Wilkinson GR. (1994). Effect of fasting and
obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of
CYP2E1 activity. The Journal of Pharmacology and Experimental Therapeutics.
56:359-367.

Piao YF, Li JT and Shi Y. (2003). Relationship between genetic polymorphism of
cytochrome P450IIE1 and fatty liver. World Journal of Gastroenterology. 9:
2612-2615.

Poschl G and Seitz HK. (2004). Alcohol and cancer. Alcohol&Alcoholism.
39: 155-165.

Takeshita T, Morimoto K, Mao XQ, Hashimoto T and Furuyama J. (1993).
Phenotypic differences in low Km aldehyde dehydrogenase in Japanese workers.
Lancet. 341: 837-838.

Thomasson HR, Crabb DW, Edenberg HJ, Li TK, Hwu HG, Chen CC, Yeh EK and
Yin SJ. (1994). Low frequency of the ADH2*2 allele among Atayal natives of
Taiwan with alcohol use disorders. Alcoholism,Clinical and Experimental
Research. 18: 640-643.

Umeno M, McBride OW, Yang CS, Gelboin HV and Gonzalez FJ. (1988). Human
ethanol-inducible P4502E1: complete gene sequence, promoter characterization,
chromosome mapping, and cDNA-directed expression. Biochemistry. 27:
9006-9013.

Wakabayashi I, Kobaba-Wakabayashi R and Masuda H. (2002). Relation of drinking
alcohol to atherosclerotic risk in type 2 diabetes. Diabetes Care. 25: 1223-1228.

Wang SL, Lee H, Chen KW, Tsai KJ, Chen CY and Lin P. (1999). Cytochrome
P4502E1 genetic polymorphisms and lung cancer in a Taiwanese population.
Lung Cancer. 26: 27-34.

Wu MS, Chen CJ, Lin MT, Wang HP, Shun CT, Sheu JC and Lin JT. (2002). Genetic
polymorphisms of cytochrome p450 2E1, glutathione S-transferase M1 and T1,
and susceptibility to gastric carcinoma in Taiwan. International Journal of
Colorectal Disease. 17: 338-343.

Yin SJ, Han CL, Lee AI and Wu CW. (1999). Human alcohol dehydrogenase family,
Functional classification, ethanol/retinol metabolism, and medical implications.
Advance in Experimental Medicine and Biology. 463: 265-274.

Yu MW, Gladek-Yarborough A, Chiamprasert S, Santella RM, Liaw YF and Chen
CJ. (1995). Cytochrome P450 2E1 and glutathione S-transferase M1
polymorphisms and susceptibility to hepatocellular carcinoma. Gastroenterology. 109: 1266-1273.

樊台聖、李一靜、陳秀卿、趙善如、范慧華, 民國九十年, 原住民生活型態
與健康問題調查. 屏東科技大學學報第十卷第二期159-171頁.

柴國樑、郝立智, 2004年, 漫談脂肪肝. 台灣醫界第 47卷第一期13-17頁.