As a person starts drinking alcohol, up to 5% of the ingested ethanol is directly absorbed and metabolized by some of cells of the gastrointestinal tract (the mouth, tongue, esophagus and stomach). Up to 100% of the remaining ethanol travels in circulation. This is one reason why blood tests are more accurate in measuring alcohol levels.
The lungs and kidneys will excrete about 2% to 10% of this circulatory ethanol. The more you drink the more quick trips to the restroom. The human body dehydrates as a result of these frequent trips to the restroom. This dehydration affects every single cell in your body, including your brain cells. This is the cause of the so-called “morning hangover”. Do not take Tylenol (acetaminophen). Alcohol metabolism activates an enzyme that transforms acetaminophen into a toxic metabolite that causes liver inflammation and damage. Liver damage may not be irreversible. Instead, drink water with electrolytes or sport drinks to rehydrate the body’s cells.
Alcohol is a volatile (flammable) organic substance and can be converted to a gas. The lungs exhale alcohol as a gas. The more alcohol consumed, the stronger the smell of alcohol in a person’s breathe. Breathalyzer tests measure the exhaled alcohol levels in the lungs to determine the state of inebriation.
The liver metabolizes up to 85% - 98% of the circulatory ethanol. The liver uses two metabolic processes to get rid of this circulatory ethanol as quickly and safely as possible.
- Alcohol dehydrogenase system
- Microsomal ethanol oxidizing system (MEOS)
Alcohol Dehydrogenase System
About 80 to 90% of the total hepatic ethanol uptake is processed via the alcohol dehydrogenase system. The reminder 10 to 20% of the total hepatic ethanol uptake is processed via the microsomal ethanol oxidizing system (MEOS).
The degradation of ethanol begins in the cytosol of the hepatic cell. The main cytosolic enzyme that catalyzes this reaction is called alcohol dehydrogenase. The products from this reaction are acetaldehyde, NADH and H+ ion. Acetaldehyde is very toxic to the liver and the body’s cells. The moment acetaldehyde is produced; it must be degraded to protect the liver cells. The enzyme that will carry this type of degradation reaction is acetaldehyde dehydrogenase (ALDH). Acetaldehyde dehydrogenase is found in both the mitochondria (ALDH2) and the cytosol (ALDH1) of the hepatic cells. Most of the hepatic acetaldehyde is then transported to the mitochondria for further degradation. A small portion is degraded in the cytosol of the hepatic cells. Acetaldehyde dehydrogenase converts acetaldehyde into acetate, a non-toxic molecule. Other products from this reaction are NADH and H+ ion.
Microsomal Ethanol Oxidizing System (MEOS)
In a moderate drinker, about 10 to 20% of the total hepatic ethanol uptake is processed via the microsomal ethanol oxidizing system (MEOS). During periods of heavy drinking, the MEOS system will metabolize most of the excess ethanol ingested. Heavy drinking stimulates the synthesis of all cytochrome P450 enzymes in the human body to include the MEOS system enzymes. This will help clear ethanol faster from the body.
The MEOS system is located on the membrane of the endoplasmic reticulum (inside the cytosol of the hepatic cell) and contains a cytochrome P450 enzyme complex. The enzyme complex is made up of two subunits: a cytochrome P450 reductase and a cytochrome P450 (also known as CYP2E1). Oxygen gas (O2 ) binds the iron-heme of the cytochrome P450 (CYP2E1). This activates the cytochrome P450 (CYP2E1) to accept electrons from NADPH. The cytochrome P450 reductase first transfers these two electrons from NADPH to the iron-heme of the cytochrome P450 (CYP2E1). Ethanol binds the other binding site of cytochrome P450 (CYP2E1) and is converted to acetaldehyde. This acetaldehyde is then further degraded by cytosolic (ALDH1) and mitochondrial (ALDH2) acetaldehyde dehydrogenase. Acetaldehyde dehydrogenase immediately converts acetaldehyde into acetate, a non-toxic molecule. Other products from this reaction are NADH and H+ ion.
Fate of Acetate
The acetate produced (from the alcohol dehydrogenase system and microsomal ethanol oxidizing system) is either released into circulation (major) or retained inside the liver cells (minor).
In the cytosol of the hepatic cells, acetate is converted to acetyl CoA. The enzyme responsible for this reaction is acetyl CoA synthetase. The acetyl CoA can:
- Enter the TCA cycle to produce CO2, FADH2, three molecules of NADH and three H+ ions.
- Be used in the synthesis of fatty acids and cholesterol.
In circulation, acetate is taken up by skeletal muscle, heart muscle and other tissue cells. Acetate is converted to acetyl CoA. The enzyme responsible for this reaction is acetyl CoA synthetase. Acetyl CoA enters the TCA cycle to produce CO2, FADH2, three molecules of NADH and three H+ ions. As the levels of CO2 begin to increase, the blood pH begins to decrease.
Excess Acetaldehyde and Generation of Radicals
A small amount (up to 10%) of the hepatic acetaldehyde may accumulate inside the liver cells. As more alcohol is ingested, this stimulates both the synthesis of the cytochrome P450 enzymes in the MEOS system and the production of acetaldehyde by both the alcohol dehydrogenase and microsomal ethanol oxidizing systems. The mitochondrial enzyme acetaldehyde dehydrogenase cannot convert this excess acetaldehyde into acetate as fast as it is produced.
Excess cytochrome P450 enzyme complexes can also generate radicals in the cytosol of the hepatic cells with increasing alcohol consumption. Ethanol induces the generation of free radicals from both the cytochrome P450 reductase and cytochrome P450 (CYP2E1) enzymes. The free radicals are called hydroxyethyl (CH3 CH2 O∙) radicals.
As the levels of acetaldehyde and radicals (CH3 CH2 O∙) increase inside the liver cells with heavy consumption of alcohol, some of the acetaldehyde and free radicals diffuse into circulation. In circulation, high levels of acetaldehyde cause nausea and vomiting. Vomiting causes more body dehydration and loss of electrolytes. If the dehydration becomes severe enough, this can impair brain function and a person may lose consciousness. As the body continues to lose water volume, the blood becomes more concentrated with alcohol and acetaldehyde resulting in alcohol intoxication, a lethal condition. A person should seek medical attention immediately to prevent death.
Accumulation of both acetaldehyde and free radicals (CH3 CH2 O∙) causes damage to the body’s cells. Acetaldehyde binds amino acid side groups, sulfhydryl groups, nucleotides (RNA & DNA bases) and phospholipids (cell membrane components) in the human body. It affects all the proteins in the human body to include proteins in the liver and the heart. In the liver, it affects the release of plasma proteins (albumin, blood coagulation factors, and transport proteins) and VLDL particles into circulation. Accumulation of both plasma proteins and lipid draws water inside the hepatic cell. Swelling of the hepatic cells impairs cell function and blood flow via the hepatic portal vein (portal hypertension).
Acetaldehyde also binds antioxidant systems in the body to include glutathione and free-radical defense enzymes. This enhances the formation of more radicals in the human body and the activation of potential toxins and carcinogens. Excess radicals generated from both acetaldehyde binding to antioxidant systems and the induction of the MEOS system cytochrome P450 enzymes will attack phospholipids in any cell membrane to include mitochondrial membranes. In the liver, peroxidation of the phospholipids in the inner mitochondrial membrane causes:
- Inhibition of the electron transport chain and uncoupling of oxidative phosphorylation. This causes inflammation and cell necrosis as a result of no ATP synthesis.
- Inhibition of β-oxidation of fatty acids. Increase synthesis and storage of lipids in the cytosol of the hepatic cells
- Damage to the alcohol dehydrogenase system as the mitochondria degrades. This leads to increase build up of both acetaldehyde and radicals by the MEOS system.
- The urea cycle is affected as the mitochondrion degrades. This releases toxic levels of ammonia into circulation (hyperammonemia).
- As the cells begin to rupture or die, bilirubin cannot be conjugated inside the liver cells. Bilirubin is released into circulation and accumulates inside the lipid membranes of the cells. This condition is known as jaundice.
Any of these effects may result in cirrhosis of the liver, hepatocarcinomas or alcohol-induced hepatitis. The transport of both acetaldehyde and free radicals (CH3 CH2 O∙) in circulation causes damage to other cells in the peripheral tissues. This may cause lung or breast cancer.
Original Source: http://cnx.org/contents/hZVLzuxa@4/Ethanol-Metabolism
High levels of NADH
NADH is a by-product of both the alcohol dehydrogenase system (alcohol dehydrogenase and acetaldehyde dehydrogenase reactions) and the degradation of acetate via the tricarboxylic acid cycle reactions. NADH accumulates inside the cytosol and the mitochondria of the hepatic cells. High levels of NADH do not inhibit the enzymes of the alcohol dehydrogenase system. Accumulated mitochondrial NADH feeds directly into the electron transport chain and oxidative phosphorylation to generate ATP. This ATP meets the energy requirements of the hepatic cells. Since there are not energy needs to be met inside the hepatic cells, β-oxidation of fatty acids is inhibited. Fatty acids accumulate inside the liver cells and are used for the synthesis of lipids and ketone bodies.
High levels of NADH also inhibit the cytosolic enzyme glyceraldehyde-3-phosphate dehydrogenase in glycolysis. Glyceraldehyde-3-phosphate (G-3-P) cannot be converted into 1, 3-bisphosphoglycerate. Instead, glyceraldehyde-3-phosphate is converted to dihydroxyacetone phosphate (DHAP). High levels of NADH stimulate the conversion of dihydroxyacetone phosphate (DHAP) to glycerol-3-phosphate. The accumulated glycerol-3-phosphate is then used for the synthesis of lipids inside the liver cells.
Hepatic Accumulation of Lipids
Alcohol stimulates the release of epinephrine from the adrenal medulla. Epinephrine levels in circulation stimulate the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH also stimulates the release of cortisol from the adrenal gland. Epinephrine binding to α-receptors in the liver cells stimulates the release of glucagon from the pancreas. Glucagon and epinephrine stimulate glycogenolysis via cAMP and inositol-phospholipid signal cascades; while, cortisol stimulates gluconeogenesis in the liver cells. Epinephrine also stimulates lipolysis in adipose tissue. Triglycerides are broken down in adipose cells and released into circulation as glycerol and fatty acids. Glycerol and fatty acids travel to the liver.
Glycerol is first converted to glycerol-3-phosphate by glycerol kinase. The conversion of glycerol-3-phosphate to dihydroxyacetone phosphate (DHAP) in gluconeogenesis is inhibited by the high levels of NADH. Because glycerol cannot be used to make glucose, the liver is unable to synthesize and release glucose into circulation. This causes hypoglycemia. The accumulated glycerol-3-phosphate is then used for the synthesis of lipids inside the liver cells.
High levels of NADH stimulate the synthesis of lipids in the cytosol of the liver cells. Fatty acids are first converted to fatty acyl CoA by the outer mitochondrial enzyme acyl CoA synthase. Some of the fatty acyl CoA molecules will be used in the synthesis of triglycerides in the cytosol; while, other fatty acyl CoA molecules will be used to synthesize ketone bodies inside the mitochondria.
Alcohol stimulates the synthesis of the enzyme fatty acyl CoA transferase. This enzyme is found in the membrane of endoplasmic reticulum and catalyzes the synthesis of triglycerides in the cytosol of the liver cells. Triglycerides are synthesized from glycerol-3-phosphate and fatty acyl CoA. A portion of these newly synthesized triglycerides are stored inside the hepatic cells; while, the remainder of these triglycerides are converted to very low density lipoprotein (VLDL). The increased accumulation of both stored triglycerides and VLDL particles inside the hepatic cells causes a condition called fatty liver or hepatic steatosis. This can impair normal liver function. The more alcohol consumption, the more lipids produced and stored inside the liver cells. These effects are cumulative over time.
As the liver cells release VLDL particles into blood circulation, this increases the levels of VLDL particles in blood. As VLDL particles continue to accumulate in blood, this cause a condition called hyperlipidemia. In their journey through circulation, VLDL particles are eventually degraded to low density lipoproteins (LDL) particles. LDL particles are also known as “bad cholesterol”. Higher levels of LDL particles in circulation lead to the build-up of cholesterol deposition plaques inside the walls of the blood vessels (known as atherosclerosis). These plaques can impair or stop blood flow to the cells. If an artery is blocked, the cells cannot make enough energy and eventually stop working. If the artery remains blocked for more than a few minutes, the cells may die. This is why immediate medical treatment is absolutely necessary. When a cardiac artery is blocked, this causes a heart attack (acute myocardial infarction). Depending on the length and severity of the blockage, damage to the cardiac cells may be permanent and irreversible. Once the heart structure and function is compromised, the more susceptible a patient would be to suffer a second heart attack.
Hepatic Accumulation of Ketone Bodies
As fatty acids are first converted to fatty acyl CoA by the outer mitochondrial enzyme acyl CoA synthase, some of the fatty acyl CoA molecules cross the outer mitochondria membrane. The outer mitochondrial enzyme carnitine:palmitoyl transferase I (CPTI) converts fatty acyl CoA to fatty acylcarnitine. The inner mitochondrial enzyme carnitine:acylcarnitine translocase pushes this fatty acylcarnitine molecule inside the mitochondrial matrix in exchange for carnitine outside the mitochondrial matrix. The inner mitochondrial enzyme carnitine:palmitoyl transferase II (CPTII) converts fatty acylcarnitine back to fatty acyl CoA inside the mitochondrial matrix.
Inside the mitochondrial membrane, fatty acyl CoA will undergo β-oxidation to produce several molecules of acetyl CoA, FADH2 and NADH. The high levels of NADH, produced from the degradation of acetate via the tricarboxylic acid cycle and this β-oxidation of fatty acyl CoA inside the mitochondria, stimulates the synthesis of malate from oxaloacetate in the tricarboxylic acid cycle. The first reaction catalyze by citrate synthase in the tricarboxylic acid is now inhibited. There is not enough oxaloacetate to react with acetyl CoA. Acetyl CoA cannot enter the tricarboxylic acid cycle and is used for the synthesis of ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate). The amount of ketone bodies produced is a lot of higher than under normal fasting conditions. The ketone bodies are then released into circulation.
The peripheral cells (skeletal muscle and other cells) will use acetate (from alcohol degradation) for energy than ketones bodies. Remember, acetate is converted to acetyl CoA. Acetyl CoA enters the TCA cycle to produce CO2, FADH2, three molecules of NADH and three H+ ions. As the levels of CO2 begin to increase, the blood pH begins to decrease. Under acidic blood conditions, ketone bodies are found in their acidic form as ketoacids. This causes a condition known as alcoholic ketoacidosis (metabolic acidosis).
Hepatic Accumulation of Lactate
Consumption and metabolism of ethanol causes high levels of NADH in the cytosol and mitochondria of the liver cell. High levels of NADH stimulate the synthesis of lactate from pyruvate via the hepatic enzyme lactate dehydrogenase. Under acidic blood conditions, lactate is found in its acidic form as lactic acid. This causes a condition known as lactic acidosis (metabolic acidosis).
The build-up of lactate/lactic acid affects the excretion of uric acid by the kidneys. Uric acid accumulates in blood (hyperuricemia). In patients suffering from gout, uric acid may accumulate and form crystals in their joints during these acidic body conditions. It is advisable that patients with gout should not drink excessively.
Hypoglycemia in the Fasting State
Consumption and metabolism of ethanol causes high levels of NADH in the cytosol and mitochondria of the liver cell. When people drink alcohol without eating, the high levels of NADH affect gluconeogenesis in the following manner:
- Single amino acids (serine, threonine, cysteine and alanine) are first converted to pyruvate. The enzyme lactate dehydrogenase converts all this pyruvate into lactate. Pyruvate cannot enter gluconeogenesis. The build-up of lactate causes lactic acidosis.
- Glycerol is first converted to glycerol-3-phosphate by glycerol kinase. The conversion of glycerol-3-phosphate to dihydroxyacetone phosphate (DHAP) is inhibited. Glyceraldehyde-3-phosphate is used in the synthesis of lipids inside the hepatic cells. This contributes to fatty liver or hepatic steatosis.
- Mitochondrial oxaloacetate from the tricarboxylic acid cycle (TCA) is converted to malate. Malate enters the cytoplasm of the hepatic cell. The conversion of malate to oxaloacetate in the cytosol of the liver cell is inhibited. Oxaloacetate cannot enter gluconeogenesis.
Because glycerol, single amino acids, and oxaloacetate cannot be converted to glucose via gluconeogenesis, the liver is unable to synthesize and release glucose in circulation. All these factors are responsible for low glucose levels in blood (hypoglycemia).
Transient Hyperglycemia in the Fed State
Consumption and metabolism of ethanol causes high levels of NADH in the cytosol of the liver cell. When you eat a meal with alcohol, the high levels of NADH inhibit the cytosolic enzyme glyceraldehyde-3-phosphate dehydrogenase in the glycolytic pathway (glycolysis). This stops the breakdown of glucose in glycolysis and causes the build-up of glyceraldehyde-3-phosphate (intermediate of glycolysis). Glyceraldehyde-3-phosphate is then converted to dihydroxyacetone phosphate (DHAP). High levels of NADH stimulate the conversion of dihydroxyacetone phosphate (DHAP) to glycerol-3-phosphate. Glyceraldehyde-3-phosphate is used in the synthesis of lipids inside the hepatic cells. This contributes to fatty liver or hepatic steatosis.
Glucose cannot be converted to pyruvate and used to generate ATP as a result. As glucose begins to accumulate in the cytosol of the hepatic cells, it is released into circulation via the hepatic glucose transporters (GLUT#s). This builds-up the glucose levels in circulation, causing hyperglycemia. Glucose will travel in circulation until the peripheral cells uptake and use this glucose for their metabolic pathways.