Ethanol Metabolism

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

Production and absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion 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 Synthesis Polymerase Chain Reaction (PCR)
  • Glycerolipid metabolism
  • Bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy acid biosynthesis Biosynthesis The biosynthesis of peptides and proteins on ribosomes, directed by messenger RNA, via transfer RNA that is charged with standard proteinogenic amino acids. Virology pathways 
• Also enters the body via alcohol consumption:
  1. Alcohol is consumed → enters the stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach: Anatomy and small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy → 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 (given a fixed quantity of ethanol) than men due to a higher percentage of body fat
  3. Via the portal system → reaches the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy, responsible for most of its metabolism

Ethanol Metabolism

The primary site of alcohol catabolism is the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy.

1. Ethanol → acetaldehyde
   • Occurs in the cytoplasm
   • Hepatic enzyme: alcohol dehydrogenase (ADH) 
     • Responsible for the bulk of ethanol breakdown into acetaldehyde
     • Found in the cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton
     • Requires ( nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway) NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway+
   • Hepatic cytochrome: P450 enzyme CYP2E1 (also called microsomal ethanol oxidizing system (MEOS))
     • Induced during chronic alcohol consumption
     • Found in microsomes
     • Requires nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes ( NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway)
     • Releases reactive oxygen species Reactive oxygen species Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids; proteins; and lipids. Nonalcoholic Fatty Liver Disease → alcoholic Alcoholic Persons who have a history of physical or psychological dependence on ethanol. Mallory-Weiss Syndrome (Mallory-Weiss Tear) liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy damage
   • Fatty acid ethyl ester (FAEE) synthase 
     • Catalyzes the reversible reaction of long-chain fatty acyl ethyl ester and H₂O ↔ long-chain fatty acids Long-chain fatty acids Digestion and Absorption and ethanol
     • Found in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy and pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy
2. Acetaldehyde → acetate: catalyzed by the acetaldehyde dehydrogenase (ALDH) enzyme
   • ALDH is found mainly in hepatic mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles, and (to a lesser extent) in the cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton.
   • Requires NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway+
3. Acetate → acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle: catalyzed by ATP–dependent acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle synthetase (ACS)
   • ACS is found in mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles and cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton.
   • Requires coenzyme A and ATP 
4. Acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle → several metabolic pathways:
   • Citric acid cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation
   • Fatty acid synthesis Synthesis Polymerase Chain Reaction (PCR)
   • Ketone body synthesis Synthesis Polymerase Chain Reaction (PCR) or ketogenesis Ketogenesis Ketone Body Metabolism
   • Mevalonate Mevalonate Cholesterol Metabolism pathway 
   • Acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS synthesis Synthesis Polymerase Chain Reaction (PCR)
   • Melatonin synthesis Synthesis Polymerase Chain Reaction (PCR)

Medications that affect ethanol metabolism

Many common medications can inhibit enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes involved in the metabolism of ethanol, leading to the accumulation of toxic products (e.g., acetaldehyde):

Excessive Ethanol Consumption

Excessive ethanol consumption, such as in alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. 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 Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics and/or vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia
  • Increased heart rate Heart rate The number of times the heart ventricles contract per unit of time, usually per minute. Cardiac Physiology
• Increase in the NADH/ NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺ ratio → excess NADH 
  • Inhibits citric acid cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation + increased acetate conversion to acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle → increase in acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle → stimulates fatty acid synthesis Synthesis Polymerase Chain Reaction (PCR) + inhibits beta oxidation Beta oxidation Fatty Acid Metabolism → fatty liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease
  • Stimulates glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis + inhibits gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis → severe hypoglycemia Severe Hypoglycemia Hypoglycemia
  • Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis:
    • Increased conversion of pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis into lactate → lactic acidosis Lactic Acidosis Oxazolidinones
    • Increased acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle → increased ketogenesis Ketogenesis Ketone Body Metabolism → ketoacidosis Ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Metabolic Acidosis

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 Abdominal Pain Acute Abdomen, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and, possibly, death.