Genetic Factors in Alcohol Metabolism and Alcoholism

Abstract

The factors that govern blood and tissue concentrations of ethanol after its ingestion are the rate of absorption from the gastrointestinal tract, the space of distribution in the body, and the rate of elimination. Ethanol is absorbed rapidly by diffusion from the stomach and small intestines and is distributed in total body water. It is neither accumulated to any extent by specific organs nor preferentially bound to cellular components. It is eliminated almost entirely by oxidative metabolism in the liver. Consequently, after an initial equilibration phase, the primary determinant of the duration and extent of ethanol's pharmacologic and potentially pathologic effects is the rate of its oxidative metabolism. For this reason, the enzymatic pathways of ethanol metabolism and their control by genetic and environmental factors have been important areas for detailed study. This review focuses on recent gains in our knowledge of the biochemical genetics of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), the two principal enzymes of ethanol oxidation in liver, and discusses the relationship of the discovered genetic polymorphisms of these enzymes to individual differences in alcohol oxidizing capacity and to alcohol abuse liability. GENETIC INFLUENCE ON ETHANOL PHARMACOKINETICSIn the fasted state, ingested ethanol is absorbed principally from the duodenum and jejunum, owing to its rapid transit through an empty stomach.When ethanol is consumed with food or when the stomach is already full, substantial amounts of ethanol are absorbed from the stomach. As much as 70% of the ingested ethanol can be From the absorbed from the stomach under these conditions and absorption may not be completed until 4 to 5 hours after ingestion.' Foodstuffs such as fats and hypertonic solutions delay gastric emptying. Delayed absorption leads to a lesser amount of ethanol appearing in the systemic circulation, because there is more time for first-pass metabolism to occur.2 This is the metabolism of ethanol by enzymes in the gastric and intestinal mucosa and the liver, as ethanol is absorbed and passes via the portal circulation through the liver to the systemic circulation. The rate of ethanol absorption is partially determined by genetic factor^,^ although the mechanism for this effect is unknown.After the absorptive and distributive phases are complete, rates of ethanol elimination can be estimated by measuring ethanol concentrations in the blood or breath over time. There is still lack of general agreement on what are the best ways to perform such calculations, because ethanol can be metabolized by different enzyme systems that have different affinities for ethanol (vide infra). However, experimental studies in humans can be performed only over a limited range of ethanol concentrations with safety. Under these circumstances, the rate of disappearance from blood or breath in the postabsorption-distribution phase can usually be described adequately by a single compartment model with pseudozero order (Widmark) or single K, Mic...

Polymorphisms of Alcohol Metabolizing Enzymes in Indigenous Mexican Population: Unusual High Frequency of CYP2E1*c2 Allele

“…Literature about the prevalence of ADH1B, ALDH2, and CYP2E1 gene variations has been extensive due to the important participation of the enzymes encoded by these genes in ethanol metabolism (Bosron et al, 1993;Tanaka et al, 1997). Tables 2-4 compare our results with the corresponding frequencies reported in various populations around the world.…”

Cytochrome P450 2E1 variable number tandem repeat polymorphisms and health risks: A genotype-phenotype study in cancers associated with drinking and/or smoking

“…Alcohol is metabolized by the liver cells (hepatocytes) via 3 pathways: the alcohol dehydrogenase pathway in the cytosol, the microsomal ethanol oxidizing system in the endoplasmic reticulum and catalase in the peroxisomes. All 3 pathways result in the production of acetaldehyde, which is then metabolized by aldehyde dehydrogenase (ALDH) into acetate, a metabolite more toxic than alcohol itself (2)(3)(4).…”

Alcohol Consumption Mediates the Relationship Between ADH1B and DSM-IV Alcohol Use Disorder and Criteria

“…Although many factors infl uence the risk of AUDs, the contribution of genetic factors is important. Alcohol dehydrogenase genes are among the most widely studied risk genes for AUDs (Rietschel and Treutlein, 2013) because they determine the forms of the enzymes that convert alcohol (ethanol) to acetaldehyde during alcohol metabolism (Bosron et al, 1993;Thomasson et al, 1993).…”