Lecture 3.1a - Alcohol Metabolism and oxidative stress

Ethanol Characteristics

• Ethanol is a small molecule that is both lipid and water soluble, but practically insoluble in fats and oils.
• It is transported by simple diffusion across the cell membrane.

Distribution of Ethanol in the Body

• Ethanol distributes from the blood into all tissues and fluids in proportion to their relative water content.
• Women have a smaller volume of distribution for alcohol than men due to their higher percentage of body fat.
• The equilibrium concentration of alcohol in a tissue depends on the relative water content, rate of blood flow, and the mass of that tissue.
• A woman's body is composed of approximately 45-50% water, while a man's body is about 55-65% water.
• The lower fluid volume in women results in higher concentrations of alcohol in the bloodstream compared to men.

Alcohol Absorption

• Alcohol is absorbed in the stomach and intestine tissues.
• It crosses biological membranes by simple passive diffusion, not requiring transporters or energy.
• Peak blood alcohol levels are higher if ethanol is ingested as a single dose rather than several smaller doses.
• The presence of food in the stomach retards gastric emptying, reducing the absorption of alcohol.

Alcohol Metabolism

• Most (>90%) alcohol is metabolized by the liver.
• The remainder is excreted passively in urine and on breath (10%).
• Enzymes involved in metabolism include alcohol dehydrogenase (ADH) and cytochrome P450.
• Acetaldehyde is toxic and is metabolized further by acetaldehyde dehydrogenases (ALDH) into acetate.
• Acetate is not toxic and is converted to acetyl-CoA in the skeletal muscle.
• Approximately 10-20% of ingested ethanol is oxidized through cytochrome P450 enzymes in the endoplasmic reticulum (especially CYP2E1).
• CYP2E1 has the highest activity toward ethanol and is inducible.

Liver Damage

• Alcohol-induced liver disease is a common and sometimes fatal consequence of chronic ethanol abuse.
• Forms of liver damage include fatty liver, alcohol-induced hepatitis, and alcoholic cirrhosis.
• Many toxic effects of chronic ethanol consumption result from accumulation of acetaldehyde.
• Changes in fatty acid metabolism, generation of free radicals, and chronic loss of function contribute to liver damage.

Clinical Presentation of Liver Damage

• Mechanisms of liver damage include:
  • Fatty liver: inhibition of fatty acid oxidation and stimulation of triacylglycerol synthesis, leading to more fat produced.
  • Alcoholic hepatitis: generation of free radicals from acetaldehyde.
  • Alcoholic cirrhosis: damage to hepatocytes characterized by fibrosis, abnormal blood flow, and loss of liver function.

Treatment of Alcohol Dependence

• Disulfiram is a drug used to support the treatment of alcohol use disorder.
• It inhibits aldehyde dehydrogenase, resulting in the accumulation of acetaldehyde (toxic).
• Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage.
• Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms (hangover).