Alcohol Absorption, Metabolism and Distribution

• Alcoholic beverages are primarily water, ethanol, and sugar.

Serving Sizes & Alcohol Content

• Standard servings contain roughly 14 grams of alcohol.
• Beer: 1 pint (500 mmol, ~ 2 units)
• Whiskey: 1/5 gill (250 mmol, ~ 1 unit)
• Sherry: 1 glass (325 mmol, ~ 1 unit)
• Wine: 1 glass (200 mmol, ~ 1 unit)
• One unit of alcohol is about 8g of pure alcohol, for clinical purposes.

Absorption & Excretion

• Alcohol is absorbed rapidly via simple diffusion throughout the GI tract.
• The stomach absorbs around 20% of alcohol.
• Alcohol distributes quickly throughout the body's water compartments.
• The liver metabolizes about 90% of alcohol, with 5% excreted in urine and the remaining eliminated through the lungs.

Factors Affecting Blood Alcohol Levels

• Body weight: Higher body weight and water content dilute alcohol more effectively.
• Gender: Men have more body water and stomach ADH, leading to lower blood alcohol levels than women after consuming the same amount of alcohol.
• Food: Food slows down alcohol absorption.
• Drinking rate: The body metabolizes alcohol slowly; increased drinking rate raises blood alcohol levels.
• Drink type: Alcohol content and carbonation affect absorption speed; carbonated mixers increase absorption.

Alcohol Metabolism Pathways

• There are two main pathways of alcohol metabolism.
• Cytosolic alcohol dehydrogenase (ADH) breaks down small amounts of alcohol.
• The microsomal ethanol-oxidizing system (MEOS) is used for larger alcohol amounts.
• Colon bacteria metabolize alcohol into acetaldehyde (a toxic compound) via ADH.

Ethanol Metabolism Route

• Begins in the liver with ADH converting ethanol into acetaldehyde.

• Acetaldehyde is further converted to acetate by ALDH in the liver.

• Acetate is then used by the muscle through ACS and enters the TCA cycle.

• Alcohol metabolism increases NADH concentration in the liver.

• Fomepizole blocks alcohol dehydrogenase.

• Fomepizole is the preferred antidote for methanol or ethylene glycol overdoses.

• Alcohol dehydrogenase prefers ethanol over methanol or ethylene glycol.

• Ethanol is a competitive inhibitor for alcohol dehydrogenase to treat methanol or ethylene glycol poisoning.

Alcohol Dehydrogenase (ADH)

• Is a family of isoenzymes.
• Class 1 ADHs have the highest specificity for ethanol.
• Three genes encode class 1 ADH, existing as allelic variants (polymorphisms).
• Class 1 ADH is highly concentrated in the liver, making up 3% of soluble protein.
• Class 1 ADH has a low Km, high affinity for alcohol, and plays a main role in EtOH metabolism and production of acetaldehyde.
• ADH(class iv) is found in the GIT so the acetaldehyde generated here may be associated to cancers
• ADH (Class 11) is mostly expressed on the liver and at a lower level in the lower GI tract,

Functional Polymorphisms of ADH

• ADH 1A and ADH 1C are functional polymorphisms.
• ADH 1A and ADH 1C partially explain differences in ethanol elimination rates.
• Possession of the ADH1B*2 allele (fast ADH) reduces susceptibility to alcoholism, related to acetaldehyde accumulation that causes nausea/flushing when ALDH can't keep up.
• This allele is frequent in East Asians and infrequent in white Europeans.

Acetaldehyde Dehydrogenase (ALDH)

• 80% of acetaldehyde metabolism is processed via the mitochondrial enzyme ALDH2.
• ALDH has high affinity for acetaldehyde and is very specific.
• Individuals with a ALDH2 variant have significantly reduced acetaldehyde breakdown.
• ALDH1 isoform is cytosolic.
• Acetylaldehyde accumulation results in nausea and vomiting.
• Inactive ALDH variants are associated with protection against alcoholism.
• Alcoholism can be treated with an ALDH inhibitor (Disulfiram).

Fate of Acetate

• Activation to acetyl CoA is required for acetate metabolism.
• Liver ACS1 produces acetyl CoA for cholesterol and FA synthesis in the cytosol.
• Most acetate enters the blood.
• The heart and skeletal muscle take up acetate (high ACS11 concentration).
• Acetyl CoA that enters the TCA cycle is then oxidized.

Microsomal Ethanol Oxidizing System (MEOS)

• Includes cytochrome P450 superfamily enzymes.
• The superfamily includes 10 gene families in mammals with > 100 cyt P450 isoenzymes
• MEOS collectively refers to ethanol oxidizing activity by all P450 enzymes.
• CYP2E1 has a higher Km for ethanol than class 1 ADHs.
• At high levels of EtOH consumption, a larger part of ethanol goes through CYP2E1.

Induction of P450 Enzymes

• Chronic alcohol use leads to increased hepatic CYP2E1 levels (5-10 fold).
• Other P450s also increase.
• ER proliferates.
• P450 enzymes create free radicals, causing hepatic injury.
• Overlapping specificities lead to drug interactions and major consequences, such as Phenobarbital interaction (CYP2B2) is inhibited by ethanol.

Acute Effects of Ethanol Metabolism

• Derives from increased NADH/NAD+ Ratio.
• A high ratio inhibits Fatty acids oxidation, so the FAs accumulate in liver as TAGs.
• Promotes formation of glycerol 3-phosphate from glycolysis intermediates.
• TAGs are incorporated into VLDLs, which accumulate in the liver and enter the blood, yielding ethanol-induced hyperlipidemia.

Alcohol-Induced Ketoacidosis

• Fatty acids are oxidized to acetyl-CoA then to ketone bodies.
• Oxaloacetate (OAA) converts to malate is the TCA cycle and leaves oxaloacetate levels too low for citrate synthase for which to synthesize citrate.
• Ketone bodies are produced at a very high rate so concentrations are likely much higher than normal fasting conditions.

Effects of Increased NADH/NAD+ Ratio

• Lactic acidosis: balance of LDH is shifted toward lactate, resulting in lactate acidosis.
• Hyperuricemia: may decrease excretion of uric acid by kidneys.
• Hypoglycemia: fasting individuals who are drinking depend on gluconeogenesis for blood glucose maintenance.
• Lactate and alanine major gluconeogenesis precursors enter as pyruvate.
• Ethanol consumption with a meal causes transient hyperglycemia due to inhibition of glycolysis.

Acetaldehyde Toxicity

• Many toxic effects of chronic ethanol use come from the production and accumulation of acetaldehyde from EtOH by ADHs and MEOS.
• Acetaldehyde accumulates in the liver and is released into the blood post-EtOH intake.
• It's very reactive, binding covalently to amino acids, sulfhydryl groups, nucleotides, and phospholipids, forming adducts.

Acetaldehyde & Hepatitis

• Acetaldehyde-adduct formation with AAs result in a decrease in of hepatic protein synthesis.
• Proteins in the heart are also affected.
• Decrease in tubulin synthesis causes diminished secretion of serum proteins and VLDL from liver.
• Proteins accumulate in liver along with lipid.
• Accumulation of protein causes influx of water in hepatocytes.
• Liver swells, contributes to portal hypertension and disruption of liver architecture.

Acetaldehyde and Free Radical formation

• Acetaldehyde adduct formation causes free radical damage.
• Glutathione binds directly to diminish its ability to protect against H2O2, which prevents lipid peroxidation.
• Mitochondria damage (cycle of toxicity).
• Electron Transport Chain is inhibited which uncouples oxidative phosphorylation.
• Fatty acid oxidation further decreased (lipids accumulation).

Ethanol & Free Radicals

• Increased hepatic oxidative stress is a consequence of increased free radicals from CYP2E1
• FAD/FMN in reductase and heme in cyt P450 system transfer single electrons through a mechanism that can generate free radicals.
• Induction of all P450s can cause production of free radicals from drug metabolism and toxins/carcinogens.
• Phospholipids are the main target of peroxidation by free radical release.

Hepatic Cirrhosis

• At the stage when hepatic cirrhosis develops, liver injury is irreversible.
• Liver becomes enlarged, full of fat with collagen fibers.
• In Laennec's cirrhosis, the liver shrinks.
• Normal metabolic processes are lost.

Alcoholism & Fatty Liver

• NADH levels in the liver increase.
• High NADH levels inhibit the oxidation of fatty acids.
• FAs mobilized from adipose tissue, are reesterified to glycerol 3-phosphate in the liver – forming TAGs.
• TAGs are packaged into VLDL and secreted into the blood.
• Elevated VLDL is frequently associated with chronic alcoholism.
• As alcohol-induced liver disease progresses, the ability to secrete the TAGs diminishes, which causes a fatty liver.

Physiological Impact of Alcohol Metabolism

• There is a gender disparity in metabolic effect.
• Women have lower stomach ADH activity with less body water than men.
• Alcohol metabolism by ADH promotes fat synthesis.
• Reactive oxygen molecules are generated in the MEOS pathway.

Adverse Effects of Alcohol Consumption

• Short-term effects interfere with organ function for several hours after ingestion.
• Chronic alcohol use interferes with the nutritional status and produces toxic compounds.
• The effects of alcohol vary with life stage
• When alcohol intake exceeds liver's ability to break it down, alcohol intoxication or alcohol poisoning can occur.
• Alcohol effects the central nervous system, breathing, and heart rate.

Explore alcohol absorption, distribution, and metabolism in the body. Understand ADH and MEOS pathways and the role of colon bacterial ADH. Learn about the impact of liver function and body composition on alcohol metabolism.