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 Valentin‑Domènech 2023.

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 Valentin‑Domènech 2023. 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 encodes the β‑subunit of class I alcohol dehydrogenase expressed in liver and stomach. The rs1229984 polymorphism (Arg48 → His) increases catalytic turnover 40‑100‑fold for the His allele Peng 2010. Rapid acetaldehyde generation produces an immediate aversive response (flushing, nausea, tachycardia) and lowers the risk of heavy drinking.

ALDH2 encodes the rate‑limiting mitochondrial enzyme that oxidises acetaldehyde to acetate. The rs671 variant (Glu504 → Lys; ALDH2*2) abolishes or markedly reduces enzymatic activity He 2022. Unmetabolised acetaldehyde is mutagenic and vasoactive, explaining both the acute flushing reaction and the long‑term increase in aerodigestive cancers.

Alterations in these genes shift the kinetic bottleneck of ethanol elimination. Variants in other loci may contribute but currently lack comparable effect size or reproducible evidence Walters 2023.

Genotype determines the relative flux through the ethanol→acetaldehyde→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 AUC, proportional to flushing severity, blood pressure rise and carcinogenic burden Takeuchi 2023. 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.

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)

ALDH2‑based guidance (rs671)

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.

• Valentin‑Domènech A et al. GABAergic signalling in alcohol use disorder (Front Neural Circ 2023).
• He Z et al. ALDH2 rs671 polymorphism umbrella review protocol (Syst Rev 2022).
• Walters RK et al. Genome‑wide study of alcohol flushing (BMC Genomics 2023).
• Peng Y et al. ADH1B Arg47His allele distribution (BMC Evol Biol 2010).
• Wu CY et al. Supplementary allele‑frequency tables, Taiwan Biobank (Front Pharmacol Clin 2024 supplement).
• Takeuchi F et al. ALDH2*2 and coronary artery disease (JAMA 2023).
• Kim AA et al. ADH1B*His and CDT biomarker levels (Russ J Genet 2025).