{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:46:08Z","timestamp":1790703968046,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alcoholism is a complex behavior trait influenced by multiple genes as well as by sociocultural factors. Alcohol metabolism is one of the biological determinants that can significantly influence drinking behaviors. Alcohol sensitivity is thought to be a behavioral trait marker for susceptibility to develop alcoholism. The subjective perceptions would be an indicator for the alcohol preference. To investigate alcohol sensitivity for the variants ADH1B*2 and ALDH2*2, sixty healthy young males with different combinatory ADH1B and ALDH2 genotypes, ADH1B*2\/*2\u2013ALDH2*1\/*1 (n = 23), ADH1B*2\/*2\u2013ALDH2*1\/*2 (n = 27), and ADH1B*1\/*1\u2013ALDH2*1\/*1 (n = 10), participated in the study. The subjective perceptions were assessed by a structured scale, and blood ethanol and acetaldehyde were determined by GC and HPLC after an alcohol challenge in two dose sessions (0.3 g\/kg or 0.5 g\/kg ethanol). The principal findings are (1) dose-dependent increase of blood ethanol concentration, unaffected by ADH1B or ALDH2; (2) significant build-up of blood acetaldehyde, strikingly influenced by the ALDH2*2 gene allele and correlated with the dose of ingested alcohol; (3) the increased heart rate and subjective sensations caused by acetaldehyde accumulation in the ALDH2*2 heterozygotes; (4) no significant effect of ADH1B polymorphism in alcohol metabolism or producing the psychological responses. The study findings provide the evidence of acetaldehyde potentiating the alcohol sensitivity and feedback to self-control the drinking amount. The results indicate that ALDH2*2 plays a major role for acetaldehyde-related physiological negative responses and prove the genetic protection against development of alcoholism in East Asians.<\/jats:p>","DOI":"10.3390\/biom11081183","type":"journal-article","created":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T08:57:14Z","timestamp":1628585834000},"page":"1183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Acetaldehyde Enhances Alcohol Sensitivity and Protects against Alcoholism: Evidence from Alcohol Metabolism in Subjects with Variant ALDH2*2 Gene Allele"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6319-6114","authenticated-orcid":false,"given":"Yi-Chyan","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan"},{"name":"Department of Psychiatry, School of Medicine, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Fang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Long","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Nursing and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Jiun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1001\/jamapsychiatry.2016.0360","article-title":"Alcohol Use Disorder and Mortality Across the Lifespan: A Longitudinal Cohort and Co-relative Analysis","volume":"73","author":"Kendler","year":"2016","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/acps.12330","article-title":"Mortality and life expectancy of people with alcohol use disorder in Denmark, Finland and Sweden","volume":"131","author":"Westman","year":"2015","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1172\/JCI113875","article-title":"Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2 (2) allele is dominant","volume":"83","author":"Crabb","year":"1989","journal-title":"J. Clin. Investig."},{"key":"ref_4","first-page":"113","article-title":"Alcohol dehydrogenase: Enzymology and metabolism","volume":"2","author":"Yin","year":"1994","journal-title":"Alcohol Alcohol. (Oxf. Oxfs.) Suppl."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5","DOI":"10.15288\/jsa.2000.61.5","article-title":"Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking","volume":"61","author":"Li","year":"2000","journal-title":"J. Stud. Alcohol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/j.1530-0277.2001.tb02138.x","article-title":"Genetic and environmental influences on alcohol metabolism in humans","volume":"25","author":"Li","year":"2001","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Agarwal, D.P., and Seitz, H.K. (2001). Functional polymorphism of alcohol and aldehyde dehydrogenases: Alcohol metabolism, alcoholism, and alcohol-induced organ damage. Alcohol in Health and Disease, Marcel Dekker.","DOI":"10.3109\/9780203902172"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1111\/j.1530-0277.2006.00139.x","article-title":"Functional assessment of human alcohol dehydrogenase family in ethanol metabolism: Significance of first-pass metabolism","volume":"30","author":"Lee","year":"2006","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.cbi.2008.10.029","article-title":"Polymorphism of ethanol-metabolism genes and alcoholism: Correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences","volume":"178","author":"Chen","year":"2009","journal-title":"Chem. Biol. Interact."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1111\/acer.13904","article-title":"Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review","volume":"42","author":"Edenberg","year":"2018","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1097\/00008571-199204000-00002","article-title":"Pharmacogenetics of alcohol metabolism and alcoholism","volume":"2","author":"Agarwal","year":"1992","journal-title":"Pharmacogenetics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0079-6603(08)60844-2","article-title":"Genetics of human alcohol-metabolizing enzymes","volume":"40","author":"Yoshida","year":"1991","journal-title":"Prog. Nucl. Acid Res. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Harris, H., and Hirschhorn, K. (1986). Genetics of human alcohol and aldehyde dehydrogenases. Advances in Human Genetics 15, Springer.","DOI":"10.1007\/978-1-4615-8356-1"},{"key":"ref_14","first-page":"411","article-title":"Overview of ALDH polymorphism: Relation to cardiovascular effects of alcohol","volume":"Volume 1","author":"Preedy","year":"2005","journal-title":"Comprehensive Handbook of Alcohol Related Pathology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1086\/302540","article-title":"Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism","volume":"65","author":"Chen","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1176\/ajp.152.8.1219","article-title":"Alcohol and aldehyde dehydrogenase polymorphisms and the risk for alcoholism","volume":"152","author":"Higuchi","year":"1995","journal-title":"Am. J. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1111\/j.1530-0277.1997.tb04448.x","article-title":"Polymorphism of ADH and ALDH genes among four ethnic groups in China and effects upon the risk for alcoholism","volume":"21","author":"Shen","year":"1997","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1093\/hmg\/ddm357","article-title":"Major genetic components underlying alcoholism in Korean population","volume":"17","author":"Kim","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/s41593-020-0643-5","article-title":"Genome-wide meta-analysis of problematic alcohol use in 435,563 individuals yields insights into biology and relationships with other traits","volume":"23","author":"Zhou","year":"2020","journal-title":"Nat. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1111\/j.1530-0277.1999.tb04083.x","article-title":"Alcohol metabolism and cardiovascular response in an alcoholic patient homozygous for the ALDH2*2 variant gene allele","volume":"23","author":"Chen","year":"1999","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1097\/FPC.0000000000000096","article-title":"ALDH2*2 but not ADH1B*2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge: Correlation of the pharmacokinetic and pharmacodynamic findings","volume":"24","author":"Peng","year":"2014","journal-title":"Pharmacogenet. Genom."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/0741-8329(85)90100-4","article-title":"Aldehyde dehydrogenase polymorphism and alcohol metabolism in alcoholics","volume":"2","author":"Harada","year":"1985","journal-title":"Alcohol"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/0091-3057(79)90105-9","article-title":"Relationship between facial flushing and blood acetaldehyde levels after alcohol intake","volume":"10","author":"Mizoi","year":"1979","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1097\/FPC.0b013e32832ecf2e","article-title":"Pharmacokinetic and pharmacodynamic basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele","volume":"19","author":"Chen","year":"2009","journal-title":"Pharmacogenet. Genom."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1056\/NEJM198111193052105","article-title":"Drugs to decrease alcohol consumption","volume":"305","author":"Sellers","year":"1981","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1111\/j.1530-0277.2009.01031.x","article-title":"Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor","volume":"33","author":"Arolfo","year":"2009","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1530-0277.2009.01101.x","article-title":"From herbal roots to synthetic medicines: A historical perspective","volume":"34","author":"Li","year":"2010","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/carcin\/22.3.433","article-title":"Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics","volume":"22","author":"Yokoyama","year":"2001","journal-title":"Carcinogenesis"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8306","DOI":"10.1073\/pnas.122225199","article-title":"Identification of the enzymatic mechanism of nitroglycerin bioactivation","volume":"99","author":"Chen","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1172\/JCI26564","article-title":"Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin","volume":"116","author":"Li","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1126\/science.1158554","article-title":"Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart","volume":"321","author":"Chen","year":"2008","journal-title":"Science"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1111\/acer.13628","article-title":"A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity","volume":"42","author":"Schuckit","year":"2018","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1126\/science.2882604","article-title":"Neurogenetic adaptive mechanisms in alcoholism","volume":"236","author":"Cloninger","year":"1987","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1111\/acer.12199","article-title":"Effects of family history of alcohol dependence on the subjective response to alcohol using the intravenous alcohol clamp","volume":"37","author":"Kerfoot","year":"2013","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1111\/acer.13896","article-title":"Meta-Analysis of Genetic Influences on Initial Alcohol Sensitivity","volume":"42","author":"Edwards","year":"2018","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lo, C.L., Lossie, A.C., Liang, T., Liu, Y., Xuei, X., Lumeng, L., Zhou, F.C., and Muir, W.M. (2016). High Resolution Genomic Scans Reveal Genetic Architecture Controlling Alcohol Preference in Bidirectionally Selected Rat Model. PLoS Genet., 12.","DOI":"10.1371\/journal.pgen.1006178"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1001\/archpsyc.1984.01790200061008","article-title":"Subjective responses to alcohol in sons of alcoholics and control subjects","volume":"41","author":"Schuckit","year":"1984","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1097\/FPC.0b013e3282609e67","article-title":"Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele","volume":"17","author":"Peng","year":"2007","journal-title":"Pharmacogenet. Genom."},{"key":"ref_39","first-page":"463","article-title":"Involvement of acetaldehyde for full protection against alcoholism by homozygosity of the variant allele of mitochondrial aldehyde dehydrogenase gene in Asians","volume":"9","author":"Peng","year":"1999","journal-title":"Pharmacogenetics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1001\/archpsyc.1977.01770150104012","article-title":"The effect of lithium carbonate on affect, mood, and personality of normal subjects","volume":"34","author":"Judd","year":"1977","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1530-0277.1993.tb00739.x","article-title":"Development and validation of the biphasic alcohol effects scale","volume":"17","author":"Martin","year":"1993","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0005-7967(80)90067-4","article-title":"Validation of the Sensation Scale, a measure of subjective physiological responses to alcohol","volume":"18","author":"Maisto","year":"1980","journal-title":"Behav. Res. Ther."},{"key":"ref_43","first-page":"979","article-title":"The self-rating of the effects of alcohol (SRE) form as a retrospective measure of the risk for alcholism","volume":"92","author":"Schuckit","year":"1997","journal-title":"Addiction"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/acer.12215","article-title":"Dominance of the inactive Asian variant over activity and protein contents of mitochondrial aldehyde dehydrogenase 2 in human liver","volume":"38","author":"Lai","year":"2014","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1111\/acer.13469","article-title":"Age of Drinking Initiation as a Risk Factor for Alcohol Use Disorder Symptoms is Moderated by ALDH2*2 and Ethnicity","volume":"41","author":"Luczak","year":"2017","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1530-0277.1996.tb01080.x","article-title":"Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese","volume":"20","author":"Higuchi","year":"1996","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1111\/j.1530-0277.1992.tb01907.x","article-title":"Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles","volume":"16","author":"Wall","year":"1992","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"716","DOI":"10.2174\/138920007782109797","article-title":"Brain metabolism of ethanol and alcoholism: An update","volume":"8","author":"Hipolito","year":"2007","journal-title":"Curr. Drug Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1097\/01.ALC.0000156185.39073.D2","article-title":"The role of acetaldehyde in the central effects of ethanol","volume":"29","author":"Quertemont","year":"2005","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15S","DOI":"10.1111\/j.1530-0277.2001.tb02369.x","article-title":"The role of acetaldehyde in the actions of alcohol (update 2000)","volume":"25","author":"Eriksson","year":"2001","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s42255-021-00357-z","article-title":"Brain ethanol metabolism by astrocytic ALDH2 drives the behavioural effects of ethanol intoxication","volume":"3","author":"Jin","year":"2021","journal-title":"Nat. Metab."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/8\/1183\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:43:30Z","timestamp":1760165010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/8\/1183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,10]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["biom11081183"],"URL":"https:\/\/doi.org\/10.3390\/biom11081183","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,10]]}}}