Alcohol (Ethanol)

Ethanol is a small lipophilic molecule that readily crosses biological membranes and the blood‑brain barrier. Acute exposure produces dose‑dependent euphoria, anxiolysis, motor impairment and at higher concentrations respiratory depression.¹

Although historically used as an anaesthetic and antiseptic, contemporary “use” is almost exclusively voluntary consumption for its psychotropic effects. There is no modern therapeutic indication that requires systemic ethanol, yet its adverse medical sequelae (alcohol‑use disorder, hepatotoxicity, cardiomyopathy and carcinogenesis) impose a substantial public‑health burden.

Mechanistically, ethanol potentiates γ‑aminobutyric acid type A receptors, inhibits N‑methyl‑D‑aspartate receptors and secondarily modulates dopaminergic and opioidergic signalling in the mesolimbic reward pathway.¹ Systemic clearance is dominated by a two‑step oxidative pathway: alcohol dehydrogenase (primarily ADH1B) converts ethanol to acetaldehyde, which is subsequently oxidised to acetate by mitochondrial aldehyde dehydrogenase (ALDH2).

ADH1B

ADH1B encodes the beta subunit of class I alcohol dehydrogenase, a cytosolic NAD⁺-dependent enzyme that catalyzes the oxidation of ethanol to acetaldehyde. It forms homo- and heterodimers with ADH1A and ADH1C and accounts for the majority of first-pass ethanol metabolism in liver hepatocytes. Selective cytoplasmic expression is highest in hepatocytes, with additional group enrichment in liver and adipose tissue.²

Mechanistic impact of key variants:

ADH1B*2 (rs1229984; Arg48His): The Arg to His substitution at position 48 produces an enzyme with markedly increased catalytic efficiency for ethanol oxidation. In vitro kinetic assays show that the His48 allozyme exhibits a several-fold higher V_max and lower K_m for ethanol compared with Arg48, accelerating acetaldehyde formation.³

ADH1B*3 (rs2066702; Arg370Cys): The Arg to Cys change at residue 370 reduces NAD(H) binding and lowers enzymatic activity, slowing ethanol clearance. This allele is common in individuals of African ancestry and similarly alters ethanol pharmacokinetics.⁴

Evidence linking variants to alcohol response: ADH1B*2 is consistently associated with protection against alcohol dependence, lower consumption and reduced risk of alcohol-related cancers. A Chinese cohort (n≈677) demonstrated significantly lower rates of alcoholism among His48 carriers (OR≈0.2) compared with Arg/Arg homozygotes en.wikipedia.org. Genome-wide meta-analyses confirm rs1229984 at genome-wide significance for alcohol use disorders in East Asian populations nature.com. ADH1B*3 carriers show a reduced risk of alcohol dependence in African-American families (COGA study; n≈1 436), with the Cys370 allele linked to lower odds of alcoholism (P<0.05) academic.oup.com.

Predicted response by genotype:
Arg/Arg (wild type): Standard ethanol clearance; typical acetaldehyde exposure; average risk of heavy drinking and dependence.
Arg/His (heterozygote): Rapid oxidation of ethanol to acetaldehyde; acute acetaldehyde accumulation leads to flushing, nausea and discomfort; confers partial protection against heavy use.
His/His (homozygote): Maximal enzyme activity; pronounced acetaldehyde effects; strongest protective effect against alcohol dependence en.wikipedia.org.

Quality of evidence: Mechanistic data from recombinant-enzyme and kinetic assays are robust. Clinical association evidence includes multiple large case-control and genome-wide studies across diverse ancestries, demonstrating consistent protective effects for ADH1B*2 and ADH1B*3 with high significance. Overall evidence quality is high for both biochemical mechanism and epidemiological associations bmj.com and en.wikipedia.org.

ALDH2

Function and expression: Aldehyde dehydrogenase 2 encodes a mitochondrial enzyme that catalyzes the NAD⁺-dependent oxidation of acetaldehyde to acetate, the second step in the major oxidative pathway of ethanol metabolism. It exhibits a low K_m for acetaldehyde and localizes to the mitochondrial matrix. ALDH2 is expressed ubiquitously but shows highest protein levels in liver, heart and brain, with measurable expression in kidney, lung, muscle and other tissues en.wikipedia.org.

Mechanistic impact of the Glu504Lys (rs671) variant:

• Glu504/Glu504 (ALDH2*1/*1) retains full activity.
• Glu504/Lys504 (ALDH2*1/*2) retains approximately 6 % of wild-type activity.
• Lys504/Lys504 (ALDH2*2/*2) shows negligible activity toward acetaldehyde link.springer.com and jci.org.

Evidence linking rs671 to alcohol response: Retroviral expression of ALDH2*2 in non-hepatic cells yields immunoreactive protein lacking dehydrogenase activity, confirming a dominant-negative effect on acetaldehyde clearance ncbi.nlm.nih.gov. Heterozygotes and homozygotes accumulate acetaldehyde after drinking, producing facial flushing, tachycardia, headache and nausea within 30–60 minutes. This “alcohol flush reaction” occurs in about 20–30 % of East Asians en.wikipedia.org. Case–control and meta-analyses in East Asians report a strong protective effect of the Lys504 allele against alcohol dependence and related medical diseases. Individuals carrying one or two ALDH2*2 alleles have markedly reduced risk of alcoholism compared to ALDH2*1/*1 homozygotes link.springer.com and themednet.org.

Predicted response by genotype:
ALDH2*1/*1 – Normal acetaldehyde clearance; typical tolerance to ethanol; low likelihood of flush or adverse reaction.
ALDH2*1/*2 – Severe reduction in ALDH2 activity (≈6 %); pronounced flushing, tachycardia and nausea; reduced alcohol consumption; partial protection from dependence.
ALDH2*2/*2 – Virtually no ALDH2 activity; extreme acetaldehyde buildup; intense discomfort upon any ethanol intake; near-complete protection against heavy drinking jci.org and en.wikipedia.org.

Quality of evidence: Mechanistic data derive from robust enzyme-kinetic and structural studies confirming enzyme inactivation by the Lys504 subunit. Clinical associations rest on large case-control series, genome-wide analyses and meta-analyses in East Asian cohorts, consistently demonstrating protective effects against alcohol use disorder. Evidence quality is high for both biochemical mechanism and epidemiological associations, though largely confined to populations of East Asian ancestry and may not generalize fully to other groups jci.org and link.springer.com.

Genotype determines the relative flux through the ethanol–to–acetaldehyde–to–acetate pathway. High-activity ADH1B variants accelerate acetaldehyde formation, whereas low-activity ALDH2 variants decelerate its clearance. The net effect is an elevated systemic and tissue acetaldehyde area under the curve, proportional to flushing severity, blood pressure rise and carcinogenic burden. Individuals carrying both a high-function ADH1B allele and a deficient ALDH2 allele experience the greatest peak acetaldehyde concentration and the most pronounced acute symptoms Takeuchi 2023.

ADH1B functional groups

• High function (His/His) – rapid acetaldehyde surge; intense flushing, nausea, tachycardia; markedly decreased risk of alcohol‑use disorder; elevated acetaldehyde‑mediated cancer risk if drinking persists.
• Increased function (Arg/His) – similar but attenuated acute symptoms; moderate protection against dependence.
• Normal function (Arg/Arg) – average pharmacokinetics and population‑level risk.

ALDH2 functional groups

• Poor function (Lys/Lys) – minimal acetaldehyde clearance; severe flushing, hypotension and marked carcinogenic risk; abstinence strongly advised.
• Decreased function (Glu/Lys) – partial clearance; moderate symptoms and cancer risk; attempt to minimise intake.
• Normal function (Glu/Glu) – standard clearance; population baseline risk.

Indeterminate / Not available

• Effect: unknown
• Implication: follow standard public‑health guidance on alcohol consumption

ADH1B‑based guidance (rs1229984)

Phenotype	Implication (lay)	Guideline Recommendation
High function (His/His)	Very fast acetaldehyde build‑up causing pronounced discomfort	Advise lifelong avoidance or minimal intake to limit acute toxicity and cumulative acetaldehyde exposure
Increased function (Arg/His)	Noticeable flushing and malaise at low doses	Restrict consumption to occasional low doses; monitor for hypertension
Normal function (Arg/Arg)	Average metabolic rate	Adhere to population drinking limits
Indeterminate / Not available	Unknown impact	Initiate standard guidance

ALDH2‑based guidance (rs671)

Phenotype	Implication (lay)	Guideline Recommendation
Poor function (Lys/Lys)	Severe intolerance; markedly increased cancer risk	Strongly recommend abstinence
Decreased function (Glu/Lys)	Moderate intolerance; elevated cancer risk	Limit intake as much as practicable; counsel on malignancy surveillance
Normal function (Glu/Glu)	Typical reaction profile	Population guidance
Indeterminate / Not available	Unknown impact	Initiate standard guidance

The high‑activity ADH1B*48His allele is common in East and South‑East Asia (>60 % in many Han Chinese cohorts) but is rare in Europeans (<5 %) Peng 2010. In contrast, the ALDH2*2 allele reaches ~40 % frequency in East Asians and is virtually absent elsewhere He 2022. Recent Taiwanese biobank data confirm 25.6 % ADH1B*His carriers and 27.9 % ALDH2*2 carriers in >30 000 participants Wu 2024 supplement. These population differences underpin the notable geographic variation in flushing prevalence and alcohol‑related cancer incidence.

1. Valentin‑Domènech A et al. GABAergic signalling in alcohol use disorder. Front Neural Circ. 2023.
2. Protein Atlas. ADH1B. 2023.
3. Eriksson C et al. Functional relevance of human adh polymorphism. Alcohol Clin Exp Res. 2001.
4. McCarver D et al. Alcohol dehydrogenase-2*3 allele protects against alcohol-related birth defects among African Americans. J Pharmacol Exp Ther. 1997.
5. He Z et al. ALDH2 rs671 polymorphism umbrella review protocol. Syst Rev. 2022.
6. Walters RK et al. Genome‑wide study of alcohol flushing. BMC Genomics. 2023.
7. Peng Y et al. ADH1B Arg47His allele distribution. BMC Evol Biol. 2010.
8. Wu CY et al. Supplementary allele‑frequency tables, Taiwan Biobank. Front Pharmacol Clin. 2024.
9. Takeuchi F et al. ALDH2*2 and coronary artery disease. JAMA. 2023.
10. Kim AA et al. ADH1B*His and CDT biomarker levels. Russ J Genet. 2025.