Alcohol Absorption, Excretion & Metabolism

• Alcoholic beverages primarily consist of water, ethanol, and sugar.
• Ethanol's chemical formula is CH3CH2OH.
• A standard unit of alcohol for clinical purposes is 8g.

Absorption and Excretion

• Alcohol is rapidly absorbed via simple diffusion throughout the GI tract.
• About 20% of alcohol absorption occurs in the stomach.
• Absorbed alcohol distributes quickly throughout bodily fluids.
• Approximately 90% of alcohol is metabolized in the liver.
• The rest is excreted through urine (5%) and the lungs.

Factors Affecting Blood Alcohol Levels

• Weight correlates with body water, which dilutes alcohol in the blood.
• Men generally have lower blood alcohol levels than women due to more body water and stomach ADH alcohol dehydrogenase.
• Food in the stomach slows alcohol absorption rate.
• The rate of alcohol breakdown is slow, blood alcohol increases with drinks per hour.
• Carbonated mixers cause quicker alcohol absorption.

Alcohol Metabolism Pathways

• Cytosolic alcohol dehydrogenase (ADH) breaks down small amounts of alcohol.
• The microsomal ethanol-oxidizing system (MEOS) breaks down large quantities of alcohol.
• Colon bacteria metabolize alcohol with ADH yielding acetaldehyde.
• Acetaldehyde is a toxic compound.

Ethanol Metabolism in Liver and Muscle

• Alcohol dehydrogenase (ADH) in the liver converts ethanol to acetaldehyde.
• Acetaldehyde is then converted to acetate by acetaldehyde dehydrogenase (ALDH.)
• Acetate is converted to Acetyl CoA by ACS
• Acetyl CoA is then metabolized by the TCA cycle in the muscle.
• Fomepizole blocks alcohol dehydrogenase and is used as an antidote for methanol overdose.
• Alcohol dehydrogenase has a higher affinity for ethanol than methanol or ethylene glycol.
• Ethanol can be used as a competitive inhibitor to treat methanol and ethylene glycol poisoning.
• High doses of alcohol activate MEOS, while low doses utilize alcohol dehydrogenase.

Alcohol Dehydrogenase (ADH)

• There are a family of isoenzymes.
• Class 1 ADHs have the highest specificity for EtOH
• There are 3 genes for class 1 ADH, these have allelic variations or polymorphisms.
• Class 1 ADH is highly expressed in the liver (3% of soluble protein).
• Class 1 ADH has a low Km/high affinity for alcohol.
• ADH(class iv) exists in the GIT, contributing to acetaldehyde generation.
• Acetaldehyde generated in the GIT may promote cancers.
• ADH (Class 11) expresses primarily expressed in the liver and small amounts in the lower GI tract.

Functional Polymorphisms

• ADH 1A and ADH 1C are functional polymorphisms.
• These polymorphisms partially explain varying ethanol elimination rates among people.
• The ADH1B*2 allele codes for a fast ADH and is related to decreased alcoholism susceptibility.
• Nausea/flushing from acetaldehyde accumulation when ALDH can't keep up with ADH causes decreased tolerance to alcoholism.
• This allele occurs at high frequency in East Asian individuals and low frequency in white Europeans.

Acetaldehyde Dehydrogenase (ALDH)

• Mitochondrial acetaldehyde DH (ALDH2) is responsible for 80% of acetaldehyde processing.
• ALDH enzymes exhibits high affinity and specificity.
• Individuals with an ALDH2 allelic variant exhibits diminished capacity for acetaldehyde metabolism.
• ALDH1 exists as a cytosolic version..
• Accumulation of acetylaldehyde causes nausea and vomiting.
• Inactive ALDH variants associate with protection against alcoholism.
• Some treatments for alcoholism use ALDH inhibitors.

Fate of Acetate

• Activation to acetyl CoA is required for acetate metabolism.
• Liver ACS1 produces acetyl CoA for cytosolic cholesterol and fatty acid synthesis.
• Most acetate enters the blood.
• Heart and skeletal muscle take up acetate, which have high concentrations of ACS11.
• Acetyl CoA then oxidizes and enters TCA cycle.

Microsomal Ethanol Oxidizing System (MEOS)

• MEOS includes cytochrome P450 enzymes.
• Mammals encompass 10 distinct gene families.
• Over 100 cyt P450 exist within these 10 gene families.
• MEOS refers to the combined ethanol oxidizing activity of P450 enzymes.
• CYP2E1 has a higher Km for ethanol than class 1 ADHs.
• CYP2E1 metabolizes a greater proportion of ethanol at high levels than at lower levels.

Induction of P450 Enzymes

• Chronic consumption increases hepatic CYP2E1 levels 5-10 fold.
• Other P450s are also up-regulated.
• The endoplasmic reticulum (ER) proliferates.
• P450 enzymes generate free radicals, causing hepatic injury.
• Overlapping specificities can cause drug interactions and major consequences.
• An example is the Phenobarbital interaction (CYP2B2), where ethanol acts as an inhibitor.

Acute Effects of Ethanol Metabolism

• High NADH/NAD+ ratio inhibits oxidation of fatty acids and leads to TAG accumulation in the liver.
• Synthesis of glycerol 3-P is promoted due to glycolysis intermediates.
• TAGs are incorporated into VLDLs, causing hyperlipidemia.
• FAs are oxidized to acetyl-CoA in alcohol-induced ketoacidosis.
• Acetyl CoA is then converted to ketone bodies.
• OAA levels are too low for citrate synthase to synthesize citrate as OAA converts to Malate.

Alcohol-Induced Ketoacidosis

• Ketone bodies are produced at a high rate and at higher concentrations than normal fasting.
• Shifting the balance of LDH toward lactate causes lactic acidosis.
• The kidneys excrete less uric acid, which is relevant for patients with gout.
• A fasting individual who drinks now depends on gluconeogenesis to maintain blood glucose.
• Lactate and alanine, enter as pyruvate, but a shift toward lactate can block entry.
• Ethanol consumption with food inhibits glycolysis, which causes transient hyperglycemia.

Acetaldehyde Toxicity

• Many of the toxic effects from consistent ethanol consumption stem from acetaldehyde accumulation.
• Acetaldehyde is produced from EtOH by ADHs and MEOS.
• Acetaldehyde builds up in the liver and is released into the blood post-consumption.
• Acetaldehyde is extremely reactive and forms adducts binding covalently to amino acids, sulfhydryl groups, nucleotides, and phospholipids.

Acetaldehyde and Alcohol-Induced Hepatitis

• Acetaldehyde-adduct formation with amino acids decreases hepatic protein synthesis.
• Proteins are also affected in the heart.
• Tubulin synthesis decreases, diminishing serum protein and VLDL secretion from the liver.
• Proteins and lipids accumulate in the liver.
• Protein accumulation draws water into hepatocytes.
• These effects are responsible for causing the liver to swell, contributing to portal hypertension and disrupting the liver's architecture.

Acetaldehyde and Free Radical Damage

• Acetaldehyde adduct formation induces free radical creation that can damage the liver.
• Binding with glutathione reduces the ability to protect against H2O2 and prevents lipid peroxidation.
• Mitochondrial damage occurs, creating a cycle of cellular toxicity.
• Electron transport chain (ETC) inhibits, therefore oxidative phosphorylation is uncoupled
• Fatty acid oxidation decreases while lipids accumulate

Ethanol and Free Radical Formation

• Increased production of free radicals by CYP2E1 leads to increased oxidative stress in the liver.
• Single electrons transfer from FAD and FMN in the reductase, from heme in the cyt P450 system and cause free radical release.
• Induction of P450s elevates free radical production because of drug metabolism and toxins.
• Phospholipids are the main target of peroxidation caused by free radical release.

Hepatic Cirrhosis

• Liver injury becomes irreversible when hepatic cirrhosis occurs.
• The liver enlarges, fills with fat, and is crossed with collagen fibers as cirrhosis develops.
• Laennec's cirrhosis causes a shrunken liver.
• All normal metabolic pathways from the liver are lost.

Alcoholism & Fatty Liver

• NADH levels in the liver elevate.
• High NADH levels suppress fatty acid oxidation.
• Fatty acids mobilized from adipose tissue re-esterify to glycerol 3-phosphate, forming TAGs.
• TAGs are packaged into VLDL secreted into the blood.
• Chronic alcoholism associates with elevated VLDL.
• Alcohol-induced liver disease interferes with the secretion of TAGs, therefore a fatty liver results.

Physiological Impact of Alcohol Metabolism

• Women generally have lower stomach ADH activity and less body water than men.
• Products of alcohol metabolism by ADH support fat synthesis.
• Reactive oxygen molecules are generated in the MEOS pathway.

Adverse Effects of Alcohol Consumption

• Short-term effects disturb functioning of organs for hours after ingestion.
• Consistent alcohol consumption produces toxic compounds, interfering with nutrition.
• The effects of alcohol vary depending on the stage of life.

Acute Effects of Alcohol Consumption

• Alcohol intoxication or poisoning can occur when the liver lacks the ability to process it all.
• Circulating alcohol can effect the central nervous system, breathing, and heart rate.