Recording 14-11

Ethanol Metabolism

• Ethanol Detoxification Process - Ethanol is metabolized primarily in the liver, which plays a vital role in detoxifying this substance.

  • Two main systems responsible for detoxification:

  1. ADH System (Alcohol Dehydrogenase) - This is the main pathway for ethanol metabolism, responsible for the majority of the conversion.

     • Converts ethanol to acetaldehyde quickly and efficiently, with the aid of nicotinamide adenine dinucleotide (NAD+) as a cofactor. High levels of ethanol can saturate this pathway, limiting its ability to detoxify effectively.

  2. MEOS (Microsomal Ethanol Oxidizing System) - This system becomes increasingly important during chronic alcohol consumption or in cases of acute high ethanol exposure.

     • Composed of cytochrome P450 enzymes, it contributes about 20% to detoxification under normal conditions, but its activity can increase significantly with higher ethanol exposure, up to 80% in chronic scenarios.

• Conversion Process - Acetaldehyde produced by ADH is further metabolized by Acetaldehyde Dehydrogenase (ALDH) to form acetate, which is less toxic than acetaldehyde.

  • Acetate is converted into Acetyl CoA, a crucial molecule in cellular metabolism, which enters the Krebs cycle (TCA cycle).

  • The Krebs cycle oxidizes citrate, resulting in the production of carbon dioxide (CO₂), nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FADH₂), and ATP, which are essential for cellular functions.

Impact of Ethanol on Liver Function

• Energy Production and Demand - Energy demand influences the regulation of the Krebs cycle; low activity during periods of low demand can lead to excess citrate accumulation.

  • Citrate can exit mitochondria into the cytosol and be utilized in De Novo Lipid Synthesis (DNL), leading to increased fat production in the liver.

  • Excessive ethanol consumption can lead to hepatic steatosis (fatty liver disease) by promoting fat accumulation due to increased Acetyl CoA levels and impaired fatty acid oxidation.

• Consequences of Fat Accumulation - Hepatic Steatosis: This condition represents fat accumulation in the liver due to ethanol metabolism or excessive sugar intake (especially fructose).

  • Insulin Resistance: Ethanol-induced liver damage disrupts insulin signaling pathways, contributing to metabolic syndrome characterized by increased insulin levels and reduced insulin sensitivity.

  • Increased Risk of Liver Diseases: Chronic alcohol consumption leads to conditions such as alcoholic fatty liver disease, which can progress to cirrhosis.

    • Cirrhosis constitutes scar tissue replacing healthy liver tissue, severely impairing liver functions such as protein synthesis, which includes important proteins like albumin.

    • The loss of albumin reduces oncotic pressure, leading to conditions such as edema, where fluid accumulates in tissues causing swelling.

• Acetaldehyde Toxicity - Elevated levels of acetaldehyde can bind to proteins and DNA, forming harmful adducts that impair cellular functions and are implicated in various cancers.

  • Acetaldehyde exposure can cause chronic inflammation, increasing the risk of liver damage and other systemic effects on body tissues.

  • The penetration of acetaldehyde into various cellular compartments exacerbates tissue injury, promoting ongoing inflammatory responses that can contribute to liver disease progression.

Health Implications of Chronic Alcohol Consumption

• Liver-Related Issues - Chronic alcohol consumption leads to numerous liver-related health issues, including:

  • Fatty Liver Disease: Characterized by the accumulation of fat in liver cells, impairing normal liver function and metabolism.

  • Cirrhosis: Terminal condition resulting from prolonged damage and scarring of liver tissue, severely affecting liver functions including detoxification and metabolic regulation.

  • Increased Cancer Risk: Particularly noted is the risk of liver cancer associated with alcohol-induced oxidative DNA damage, which affects cell proliferation and repair.

  • Impaired Glucose Metabolism: Chronic ethanol exposure can suppress gluconeogenesis, leading to potential hypoglycemia during fasting conditions or nutritional deficiencies.

Possible Beneficial Effects of Ethanol

• Moderate Alcohol Intake - Epidemiological studies suggest a correlation between moderate alcohol intake and lower rates of coronary artery disease and stroke, though more research is required for definitive conclusions.

  • Proposed Mechanisms:

    • Increased levels of high-density lipoprotein (HDL) associated with moderate alcohol consumption may provide protective cardiovascular benefits.

    • The presence of antioxidants (like polyphenols) in certain alcoholic beverages, such as red wine, may help reduce oxidative stress and inflammation, potentially contributing to better health outcomes.

• Risks Associated with Alcohol Consumption - While low to moderate consumption may have benefits, it is also linked to increased breast cancer risk in women and hypertension in men.

  • Individual variations in genetic predisposition, liver metabolism, and overall health complicate the potential health benefits of alcohol consumption.

  • Overall health improvements from moderate intake are not guaranteed and can significantly vary among individuals based on multiple factors, including lifestyle, diet, and genetics.

Guidelines for Safe Alcohol Consumption

• Health Canada Recommendations - Health guidelines suggest that one drink per day for women and two for men is considered moderate consumption.

  • One drink is quantified as approximately 15 mL of pure alcohol.

  • Examples of one standard drink include:

    • 45 mL of vodka (approximately 40% alcohol)

    • 150 mL of wine (approximately 12% alcohol)

    • 355 mL of beer (approximately 5% alcohol)

• Understanding Individual Differences - Individual differences in body size, composition, and metabolic rate affect the pharmacokinetics of alcohol metabolism, leading to differing tolerances and effects among individuals.

  • Factors such as sex, age, genetic factors (like polymorphisms in ADH and ALDH), and pre-existing health conditions significantly impact an individual’s response to alcohol consumption.