Alcohol

What it is

The alcohol in drinks is ethanol, formed when glucose is fermented ¹, absorbed mainly from the small intestine and distributed throughout body water ².

In the body

The liver converts ethanol to acetaldehyde, which damages DNA, and acetaldehyde to acetate ²³.

Oxidation of ethanolHepatocyte cytosol and mitochondria, then extrahepatic tissues

Ethanol
Class I alcohol dehydrogenases (ADH1A, ADH1B, ADH1C), cytosolicNAD+ to NADHCYP2E1 (NADPH, O2) and catalase (CAT, H2O2) also form acetaldehyde
Acetaldehyde
Aldehyde dehydrogenase 2 (ALDH2), mitochondrialNAD+ to NADHDisulfiramA single ALDH2*2 (rs671) subunit renders the tetramer nearly inactive
Acetate
Acetyl-CoA synthetases ACSS2 (cytosol) and ACSS1 (mitochondria)ATP to AMP and pyrophosphate, CoAThe liver releases acetate into blood; extrahepatic tissues oxidise it
Acetyl-CoA

Class I alcohol dehydrogenases catalyse most hepatic ethanol oxidation; ADH1B*2 (rs1229984) has a Vmax of 190 min⁻¹ in vitro against 5.2 min⁻¹ for ADH1B*1, yet carriers of European descent eliminate ethanol only about 14% faster ². The CYP2E1-dependent microsomal system, with a Km for ethanol of 7–11 mM against 0.5–2.0 mM for ADH in animal studies, is induced by chronic drinking ¹.

Mitochondrial ALDH2 oxidises acetaldehyde with a Km of 0.2 µM, and a single ALDH2*2 subunit (rs671, Glu504Lys) renders the tetramer nearly inactive; the allele is common in East Asia and rare elsewhere ². In carriers, blood acetaldehyde can reach 30–75 µM, against 3 µM or less in non-carriers, causing flushing, nausea, headache and tachycardia ².

Both steps reduce NAD⁺ to NADH, and the raised hepatic NADH/NAD⁺ ratio stimulates fatty acid synthesis ¹. Ethanol given with an adequate diet produced hepatic fat accumulation in all five previously abstinent alcoholics ⁴.

What studies show

Drinkers with the flushing variant have a much higher risk of oesophageal cancer than other drinkers ³. In Japanese and Taiwanese case-control studies, heterozygous drinkers had odds ratios of 3.7 to 18.1 for oesophageal squamous cell carcinoma after adjustment for intake; in non-drinkers, ALDH2 deficiency does not alter the risk ³.

Former drinkers, whose relative risk of death was 1.22 (95% CI 1.14 to 1.31), were counted as abstainers in 65 of 87 mortality cohorts ⁵. Unadjusted, the pooled curve was J-shaped: relative risk 0.86 (0.83 to 0.90) at 1.3–24.9 g ethanol a day, against 0.97 (0.88 to 1.07) after adjustment for abstainer biases and study characteristics ⁵. In an update of 107 cohorts, fully adjusted relative risks against lifetime non-drinkers were 0.93 (0.85 to 1.01) at 1.3–24.0 g a day and 1.35 (1.23 to 1.47) at 65 g or more ⁶.

References

Independent research
Teschke R. Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects Biomedicines, 2018.
doi:10.3390/biomedicines6040106 PubMed 30424581
Funding and finding
Funding
There was no funding of this article.
Finding
Narrative review. In the liver, ADH (cytosol, NAD+), the microsomal ethanol-oxidizing system with CYP2E1 (endoplasmic reticulum, NADPH and O2) and catalase (peroxisomes, H2O2) oxidise ethanol to acetaldehyde; ADH and MEOS, but not catalase, are relevant in vivo. Km for ethanol: ADH 0.5 to 2.0 mM (animal studies), MEOS 7 to 11 mM, catalase 0.6 to 10 mM. MEOS is induced by chronic alcohol consumption through increased CYP2E1 synthesis. Mitochondrial ALDH oxidises acetaldehyde to acetate, which is released into the blood and oxidised in extrahepatic tissues; ADH and ALDH both generate NADH. The raised NADH/NAD+ ratio stimulates hepatic fatty acid synthesis and alpha-glycerophosphate supply, and acetaldehyde impairs mitochondrial fatty acid oxidation.
Independent research
Edenberg HJ, McClintick JN. Alcohol dehydrogenases, aldehyde dehydrogenases, and alcohol use disorders: a critical review Alcoholism: Clinical and Experimental Research, 2018.
doi:10.1111/acer.13904 PubMed 30320893
Funding and finding
Funding
Related work in the authors' laboratory is supported by NIH Grants U10AA008401 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and U01MH109532 from the National Institute on Mental Health (NIMH) and the National Institute on Drug Abuse (NIDA).
Finding
Class I ADH1A, ADH1B and ADH1C catalyse most hepatic ethanol oxidation; cytochrome P450s and catalase make only minor contributions. In vitro at pH 7.5, ADH1B*1 Km 0.013 mM and Vmax 5.2 per min; ADH1B*2 (rs1229984, His48) Km 1.8 mM and Vmax 190 per min; ADH1B*3 (rs2066702, Cys370) found almost exclusively in people of African origin. European carriers of ADH1B*2 eliminate ethanol about 14% faster. ALDH2 is a mitochondrial homotetramer with Km for acetaldehyde 0.2 µM; blood acetaldehyde is about 3 µM or less with active ALDH2 and 30 to 75 µM or higher in ALDH2*2 carriers. ALDH2*2 (rs671) has lysine at position 504 of the precursor (487 of the mature protein); a single ALDH2*2 subunit renders the tetramer nearly inactive; disulfiram inhibits ALDH2. rs671 allele frequency 0.160 in Han Chinese in Beijing, 0.271 in Southern Han Chinese, 0.240 in Japanese in Tokyo, 0.008 or less in the African, American, European and South Asian 1000 Genomes populations. Odds ratio for alcohol dependence 0.22 in ALDH2*2 heterozygotes (meta-analysis of 22 datasets).
Independent research
Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption PLoS Medicine, 2009.
doi:10.1371/journal.pmed.1000050 PubMed 19320537
Funding and finding
Funding
The authors received no specific funding for this article.
Finding
About 36% of East Asians show facial flushing, nausea and tachycardia after drinking, predominantly from ALDH2 deficiency; at least 540 million people, about 8% of the world population, are estimated to be ALDH2-deficient. In case-control studies from Japan and Taiwan, low-activity ALDH2 heterozygotes who drink have odds ratios of 3.7 to 18.1 for oesophageal squamous cell carcinoma after adjustment for alcohol consumption; ALDH2 deficiency does not influence oesophageal cancer risk in non-drinkers.
Independent research
Lieber CS, Jones DP, DeCarli LM. Effects of prolonged ethanol intake: production of fatty liver despite adequate diets Journal of Clinical Investigation, 1965.
doi:10.1172/JCI105200 PubMed 14322019
Funding and finding
Participants
5
Funding
Supported in part by the U. S. Army Medical Research and Development Command, Department of the Army contract DA-49-193-MD-2013, and U. S. Public Health Service research grant AM 06284 from the National Institute of Arthritis and Metabolic Diseases. Lieber held a U. S. Public Health Service Research Career Development Award.
Finding
Under metabolic ward conditions, isocaloric substitution of ethanol for carbohydrate in an adequate diet, or addition of ethanol (up to 300 g per day) to it, produced fat accumulation in liver biopsies of all five subjects. In rats given 36% of energy as ethanol for 24 days, hepatic triglycerides were 89.4 mg/g against 11.3 mg/g in pair-fed controls (19 pairs); replacing the same carbohydrate with fat produced no fatty liver.
Independent research
Stockwell T, Zhao J, Panwar S, Roemer A, Naimi T, Chikritzhs T. Do “moderate” drinkers have reduced mortality risk? A systematic review and meta-analysis of alcohol consumption and all-cause mortality Journal of Studies on Alcohol and Drugs, 2016.
doi:10.15288/jsad.2016.77.185 PubMed 26997174
Funding and finding
Participants
3,998,626
Funding
This study was funded by National Institutes of Health Award # 1RO1AAO19939-02.
Finding
Of 87 studies, 65 included former drinkers and 50 occasional drinkers in the abstainer reference group; 13 were free of both biases. Without adjustment, low-volume drinkers (1.3 to 24.9 g ethanol per day) had RR 0.86 (95% CI 0.83 to 0.90) and former drinkers RR 1.22 (1.14 to 1.31) against abstainers. After adjustment for abstainer biases and study characteristics, low-volume drinkers had RR 0.97 (0.88 to 1.07).
Independent research
Zhao J, Stockwell T, Naimi T, Churchill S, Clay J, Sherk A. Association between daily alcohol intake and risk of all-cause mortality: a systematic review and meta-analyses JAMA Network Open, 2023.
doi:10.1001/jamanetworkopen.2023.6185 PubMed 37000449
Funding and finding
Participants
4,838,825
Funding
This study was partly funded by the CCSA as a subcontract for a Health Canada grant to develop guidance for Canadians on alcohol and health. Health Canada had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. CCSA staff conducted a preliminary search to identify potentially relevant articles but did not participate in decisions about inclusion/exclusion of studies, coding, analysis, interpretation of results or approving the final manuscript.
Finding
21 of 107 studies were free of abstainer bias. Low-volume drinkers (1.3 to 24.0 g per day) had RR 0.85 (95% CI 0.81 to 0.88) unadjusted, against abstainers as defined in the included studies, and 0.93 (0.85 to 1.01) against lifetime non-drinkers after full adjustment for abstainer biases and study characteristics; fully adjusted, occasional drinkers 0.96 (0.86 to 1.06); 25 to 44 g per day 1.05 (0.96 to 1.14); 45 to 64 g per day 1.19 (1.07 to 1.32); 65 g per day or more 1.35 (1.23 to 1.47). Women drinking 25 to 44 g per day had RR 1.21 (1.08 to 1.36).
Industry-funded
Millwood IY, Walters RG, Mei XW, Guo Y, Yang L, Bian Z, et al. Conventional and genetic evidence on alcohol and vascular disease aetiology: a prospective study of 500 000 men and women in China Lancet, 2019.
doi:10.1016/S0140-6736(18)31772-0 PubMed 30955975
Funding and finding
Participants
512,715
Follow-up
about 10 years, to 1 January 2017
Funding
Chinese Ministry of Science and Technology, Kadoorie Charitable Foundation, National Natural Science Foundation of China, British Heart Foundation, Cancer Research UK, GlaxoSmithKline, Medical Research Council, and Wellcome Trust. DNA extraction and genotyping was supported by grants from GlaxoSmithKline and the UK Medical Research Council. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Finding
Mean male intake was 3, 37 and 157 g per week for rs671 AA, AG and GG. Self-reported intake had U-shaped associations with stroke and myocardial infarction, lowest at about 100 g per week; genotype-predicted mean male intake (4 to 256 g per week) had none. Per 280 g per week of genotype-predicted intake: ischaemic stroke RR 1.27 (95% CI 1.13 to 1.43), intracerebral haemorrhage 1.58 (1.36 to 1.84), total stroke 1.38 (1.26 to 1.51), acute myocardial infarction 0.96 (0.78 to 1.18), systolic blood pressure +4.3 mm Hg (3.7 to 4.9). In women, few of whom drank, the genotypes were not positively associated with blood pressure, stroke or myocardial infarction. Alcohol was estimated to cause about 8% of ischaemic strokes and 16% of intracerebral haemorrhages in men.
Expert consensus
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Personal habits and indoor combustions IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, volume 100E, 2012.
PubMed 23193840
Funding and finding
Funding
This programme has been supported since 1982 by Cooperative Agreement U01 CA33193 with the United States National Cancer Institute, Department of Health and Human Services. Additional support has been provided since 1986 by the Health, Safety and Hygiene at Work Unit of the European Commission Directorate-General for Employment, Social Affairs and Equal Opportunities, and since 1992 by the United States National Institute of Environmental Health Sciences. This volume was made possible, in part, through Cooperative Agreement CR 834012 with the United States Environmental Protection Agency. The contents of this volume are solely the responsibility of the Working Group.
Finding
Alcohol consumption, ethanol in alcoholic beverages and acetaldehyde associated with the consumption of alcoholic beverages are carcinogenic to humans (Group 1). Alcohol consumption causes cancers of the oral cavity, pharynx, larynx, oesophagus, colorectum, liver (hepatocellular carcinoma) and female breast. Acetaldehyde associated with alcohol consumption causes cancers of the oesophagus and of the upper aerodigestive tract combined. Sufficient epidemiological evidence shows that humans deficient in the oxidation of acetaldehyde to acetate have a substantially increased risk of alcohol-related cancers, in particular of the oesophagus and the upper aerodigestive tract.
Independent research
Mitchell G, Lesch M, McCambridge J. Alcohol industry involvement in the Moderate Alcohol and Cardiovascular Health Trial American Journal of Public Health, 2020.
doi:10.2105/AJPH.2019.305508 PubMed 32078349
Funding and finding
Funding
Wellcome Trust Investigator Award in Humanities and Social Science (grant 200321/Z/15/Z) to J. McCambridge.
Finding
The National Institutes of Health stopped the worldwide MACH trial in 2018, announcing its end in June 2018, after an NIH Advisory Committee to the Director working group review. Approximately two thirds of the funding for this $100 million trial was provided by five global alcohol producers (Anheuser-Busch InBev, Carlsberg, Diageo, Heineken and Pernod Ricard) through the Foundation for the National Institutes of Health. Participants were to be randomised to one drink per day or none. Soliciting the funding included convincing the companies that the study design supported their commercial interests, which the authors judge intrinsically biased.
Independent research
Wood AM, Kaptoge S, Butterworth AS, Willeit P, Warnakula S, Bolton T, et al. Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies Lancet, 2018.
doi:10.1016/S0140-6736(18)30134-X PubMed 29676281
Funding and finding
Participants
599,912
Follow-up
median 7.5 years
Funding
UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council. The funders of the study did not have any role in the study design, data analysis, or reporting of this manuscript.
Finding
40 310 deaths over 5.4 million person-years. All-cause mortality was lowest at or below about 100 g of alcohol per week. Per 100 g per week higher consumption, hazard ratios were 1.14 (95% CI 1.10 to 1.17) for stroke, 1.09 (1.03 to 1.15) for heart failure, 1.24 (1.15 to 1.33) for fatal hypertensive disease and 0.94 (0.91 to 0.97) for myocardial infarction. Against >0 to 100 g per week, drinking >100 to 200, >200 to 350 and >350 g per week corresponded to about 6 months, 1 to 2 years and 4 to 5 years lower life expectancy at age 40 years.

Updated 2026-10-21