基因缺陷 台灣人不是喝酒咖 2015年08月12日 04:10 陳瑄喻／台北報導 台灣人最不能喝！美國史丹佛大學醫學院研究指出，近半台灣人體內基因缺乏乙醛去氫酶（ALDH2 Deficiency），比例全球最高，以致純酒精（乙醛）無法代謝，若每天2杯紅酒，罹患頭頸癌和食道癌的比率就比正常人高50倍。酒精進入人體後，會先由乙醇去氫酶（ADH）代謝成乙醛，再透過ALDH2代謝為醋酸，由於乙醛被列為一級致癌物，若無ALDH2協助代謝，長期累積於人體，將會提高癌症的發生率。台北醫學大學昨與史丹佛大學合辦《第一屆台灣─史丹佛ALDH2基因與人類疾病研討會》，會中美國史丹福大學醫學院高級研究員陳哲宏針對華人喝酒臉紅和口腔、食道癌的風險及保健進行演講。陳哲宏說，史丹佛研究指出，大陸有35％的民眾體內基因缺乏ALDH2，日本為30％、韓國20％，但比起這些國家，台灣卻高達47％的民眾缺乏ALDH2，是全球比率最高的國家。
原住民 沒這個問題 為何台灣人的體內基因缺乏ALDH2？陳哲宏指出，主要ALDH2缺乏症多出現在沿海地區漢人民族身上，因此像是中國大陸、日韓等國民眾都有這類基因缺陷，但台灣原住民就沒有缺乏。
罹癌比率 高出50倍「一些不合適的建議，反而提高民眾健康風險。」陳哲宏指出，常有醫師拿著美國心臟協會的建議，提醒民眾每天可小酌1至2杯紅酒，降低心血管疾病風險，但這項建議僅適合歐美民眾，並不適合缺乏ALDH2的亞洲人。陳哲宏舉例，體內缺乏ALDH2的民眾，若每天攝取14克純酒精（相當於2杯紅酒），罹患頭頸癌和食道癌的比率就比正常人高50倍，相當驚人。
20分鐘 自我檢測 陳哲宏說，目前史丹佛大學醫學院研究團隊正研發ALDH2活化劑，已篩選30萬種化學物質後發現有一種化合物（Alda）可以刺激人體內的ALDH2，目前正在第一期臨床實驗，預計5到10年後可望上市。如何自我檢測是否體內基因缺乏ALDH2？陳哲宏說，除了透過做基因檢測外，亦可將濃度較高的烈酒，倒在OK繃上，再貼到上手臂內側，經過20分鐘後，若皮膚出現紅色斑塊，體內就是缺乏ALDH2。記者實際測驗，原本喝酒就會臉紅的程小姐以及喝酒不會臉紅的廖小姐，使用這項檢驗方法實測，發現程小姐的手臂在短短10分鐘內就出現紅色斑塊，而廖小姐則都毫無反應，顯示這項檢驗方法既簡單又準確。
Che-Hong Chen, Ph.D. Senior Research Scientist Che-Hong, a molecular biologist and geneticist, has been working with Prof. Daria Mochly-Rosen's laboratory at Stanford University for the past 21 years. Che-Hong's early research includes the characterization of the first intra-cellular receptor for protein kinase C and its protein-protein interaction with other signaling molecules. Che-Hong also studied the role of ethanol-mediated cardioprotection against ischemia-reperfusion injuries. His research demonstrated that acute ethanol protects the heart from ischemic events by mimicking cardiac preconditioning. Several protein kinase C substrates involved in this ethanol-induced protective mechanism have been identified in his research; among them is an important detoxifying enzyme aldehyde dehydrogenase (ALDH). More recently, Che-Hong has been focusing on the function of ALDH multi-gene family and its association with human diseases. By high throughput screening of small molecule libraries, Che-Hong pioneered the discovery of a class of novel enzyme activators and inhibitors of aldehyde dehydrogenase (Aldas & Aldis). Many of the 19 human ALDH isoyzmes and their mutations have been implicated in diseases caused by the accumulation of toxic aldehdyes and oxidative stress. Aldas have been shown to be effective in enhancing cell's detoxifying capacity both in vitro and in vivo. The discovery of Aldas & Aldis as a unique class of enzyme modulators carries a great potential for drug development for a wide range of human diseases. Che-Hong's current research focuses on the isolation and characterization of ALDH isozyme-specific modulators and the understanding of the basic molecular interaction between ALDH and these small molecules. In addition to the study of enzyme deficiency in ALDH, Che-Hong is also interested in applying what has learned from the ALDH project to another common human metabolic enzyme deficiency of glucose-6-phosphate dehydrogenase (G6PD).
Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo. Proc Natl Acad Sci U S A. 2015 Mar 10;112(10):3074-9. Chen CH, Cruz LA, Mochly-Rosen D. Correcting a genetic mutation that leads to a loss of function has been a challenge. One such mutation is in aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2. This mutation is present in ∼ 0.6 billion East Asians and results in accumulation of toxic acetaldehyde after consumption of ethanol. To temporarily increase metabolism of acetaldehyde in vivo, we describe an approach in which a pharmacologic agent recruited another ALDH to metabolize acetaldehyde. We focused on ALDH3A1, which is enriched in the upper aerodigestive track, and identified Alda-89 as a small molecule that enables ALDH3A1 to metabolize acetaldehyde. When given together with the ALDH2-specific activator, Alda-1, Alda-89 reduced acetaldehyde-induced behavioral impairment by causing a rapid reduction in blood ethanol and acetaldehyde levels after acute ethanol intoxication in both wild-type and ALDH2-deficient, ALDH2*1/*2, heterozygotic knock-in mice. The use of a pharmacologic agent to recruit an enzyme to metabolize a substrate that it usually does not metabolize may represent a novel means to temporarily increase elimination of toxic agents in vivo.
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