Ethanol Metabolism

Ethanol is a chemical compound that is produced in small amounts within the small intestine and is also ingested from alcoholic drinks. Ethanol’s digestion involves a complex catabolic pathway that mainly takes place in the liver. Ethanol is turned into acetaldehyde, then to acetate, and finally into acetyl-CoA, which becomes a substrate for the citric acid cycle and produces energy. Excessive ethanol intake can have pathologic metabolic consequences including alcoholism, liver disease, and cancer.

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Overview

Chemical characteristics

  • Ethanol is a 2-carbon alcohol.
  • Soluble in aqueous and lipid environments due to its small size (short carbon chain) and hydroxyl group (-OH)
  • Molecular formula: CH3CH2OH
  • Colorless, volatile liquid with a slight odor
Structure of ethanol

Structure of the ethanol molecule

Image by Lecturio.

Production and absorption

  • Ethanol is produced by the gastrointestinal (GI) tract in minimal amounts through the fermentation of intestinal contents (approximately 3 g of ethanol/day).
  • Alcohol is also produced minimally by several metabolic pathways, including:
    • Fatty acid synthesis
    • Glycerolipid metabolism
    • Bile acid biosynthesis pathways 
  • Also enters the body via alcohol consumption:
    1. Alcohol is consumed → enters the stomach and small intestine → absorbed into the bloodstream (due to solubility in water)
    2. Spreads into intracellular and extracellular spaces, including fat tissue
      • Women will typically have a higher blood alcohol level than men due to a higher percentage of body fat
    3. Via the portal system → reaches the liver, responsible for most of its metabolism

Ethanol Metabolism

The primary site of alcohol catabolism is the liver.

  1. Ethanolacetaldehyde
    • Occurs in the cytoplasm
    • Hepatic enzyme: alcohol dehydrogenase (ADH) 
      • Responsible for the bulk of ethanol breakdown into acetaldehyde
      • Found in the cytosol
      • Requires NAD+
    • Hepatic cytochrome: P450 enzyme CYP2E1 (also called microsomal ethanol oxidizing system (MEOS))
      • Induced during chronic alcohol consumption
      • Found in microsomes
      • Requires nicotinamide adenine dinucleotide phosphate (NADPH)
      • Releases reactive oxygen species → alcoholic liver damage
    • Fatty acid ethyl ester (FAEE) synthase 
      • Catalyzes the reversible reaction of long-chain fatty acyl ethyl ester and H2O ↔ long-chain fatty acids and ethanol
      • Found in the liver and pancreas
  2. Acetaldehyde → acetate: catalyzed by the acetaldehyde dehydrogenase (ALDH) enzyme
    • ALDH is found mainly in hepatic mitochondria, and less in the cytosol.
    • Requires NAD+
  3. Acetate → acetyl-CoA: catalyzed by ATP–dependent acetyl-CoA synthetase (ACS)
    • ACS is found in mitochondria and cytosol.
    • Requires coenzyme A and ATP 
  4. Acetyl-CoA → several metabolic pathways:
    • Citric acid cycle
    • Fatty acid synthesis
    • Ketone body synthesis or ketogenesis
    • Mevalonate pathway 
    • Acetylcholine synthesis
    • Melatonin synthesis
Schematic diagram of the steps of ethanol metabolism

Schematic diagram of the steps of ethanol metabolism

Image by Lecturio.

Medications that affect ethanol metabolism

Many common medications can inhibit enzymes involved in the metabolism of ethanol, leading to the accumulation of toxic products (e.g., acetaldehyde):

MedicationInhibited enzymeEffects
FomepizoleAlcohol dehydrogenase (ADH)
  • Prevents the formation of acetaldehyde
  • Used as treatment for methanol or ethylene glycol poisoning
DisulfiramAcetaldehyde dehydrogenase (ALDH)Causes accumulation of acetaldehyde → hangover symptoms
    • Nausea
    • Vomiting
    • Flushing
    • Dizziness
    • Headache
    • Abdominal discomfort
  • Used as a treatment for alcohol use disorder
  • Calcium carbimide
  • Hydrogen cyanamide
  • Cephalosporins
  • Chloramphenicol
  • Ketoconazole
  • Metronidazole
  • Nitrates
  • Nitroimidazoles
  • Sulfonamide
  • Causes a “disulfiram effect”
  • Used as a treatment for various illnesses (not alcohol use disorder)
  • Concomitant use of alcohol and these medications is not recommended

Excessive Ethanol Consumption

Excessive ethanol consumption, such as in alcohol use disorder, leads to saturation of the ethanol metabolism pathway and consequent accumulation of toxic metabolites, as well as alteration of other metabolic pathways.

  • Acetaldehyde levels exceed the capacity of alcohol dehydrogenase → acetaldehyde accumulation (toxic) → hangover symptoms
    • Alcohol-related flushing
    • Headaches
    • Nausea and/or vomiting
    • Increased heart rate
  • Increase in the NADH/NAD+ ratio → excess NADH 
    • Inhibits citric acid cycle + increased acetate conversion to acetyl-CoA → increase in acetyl-CoA → stimulates fatty acid synthesis + inhibits beta oxidation → fatty liver disease
    • Stimulates glycolysis + inhibits gluconeogenesis → severe hypoglycemia
    • Metabolic acidosis:
      • Increased conversion of pyruvate into lactate → lactic acidosis
      • Increased acetyl-CoA → increased ketogenesis → ketoacidosis
Excessive ethanol consumption

Excessive ethanol consumption

Image by Lecturio.

Clinical Relevance

The following conditions are associated with excessive ethanol consumption:

  • Alcohol use disorder: a level of alcohol consumption that exceeds the sociocultural standard. Marked by mental and physical addiction associated with an irresistible desire for the substance and drug tolerance that leads to increases in dosage and withdrawal symptoms during abstinence. 
  • Alcoholic liver disease: a range of progressive liver conditions caused by chronic and excessive alcohol consumption. Typically involves inflammation and enlargement of the liver and ends in cirrhosis. Symptoms include jaundice (yellowing of skin), intestinal bleeding, weakness, ascites (abdominal swelling), and weight loss. 
  • Fatty liver disease: the accumulation of triglycerides and other fats in hepatocytes, which leads to microvesicular and macrovesicular fatty changes seen on liver biopsy. Etiologies include alcoholic liver disease, diet, and drug-induced changes.
  • Cirrhosis: a late-stage condition caused by chronic damage to the liver, characterized by hepatic parenchymal necrosis, fibrosis of liver tissues, and an inflammatory response to the underlying cause such as chronic alcoholism. Symptoms include itchy skin, jaundice, ascites, and cancer. 
  • Hypoglycemia: an abnormally low level of glucose in the blood (< 70–110 mg/dL). Symptoms include sweating, trembling, dizziness, inability to concentrate, and nausea. Severe hypoglycemia can lead to confusion, convulsions, coma, and death.
  • Metabolic acidosis or alcoholic ketoacidosis: a reduction in the concentration of bicarbonate ions (HCO3-) that results in a blood pH < 7.35. Can occur due to excess hydrogen ions or loss of bicarbonate. This leads to abnormal breathing, “fruity breath,” abdominal pain, vomiting, and, possibly, death.

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