Alcoholic Beverage Composition

• Alcoholic beverages primarily consist of water, ethanol, and sugar

Energy, Carbohydrate, and Alcohol Content in Beverages

• Long Island iced tea contains 170 kcals of energy, 24.3g of carbohydrates and 17.8g of alcohol per 7 fluid oz serving.
• Gin and tonic contains 114 kcals, 10.5g carbohydrates and 10.7g alcohol per 10 fluid oz serving.
• Wine cooler: 170 kcals, 20.2g carbohydrates, 13.2g alcohol per 12 fluid oz.
• Beer: 146 kcals, 13.2g carbohydrates, 12.8g alcohol per 12 fluid oz.
• Light beer: 100 kcals, 4.6g carbohydrates, 11.3g alcohol per 12 fluid oz.
• White and red wine both have ~100 kcals and 13.7g alcohol per 5 fluid oz serving, but white wine has 1.2g carbohydrates while red wine has 2.5g.
• Bourbon, whiskey, and vodka all have 96 kcals and 13.9g alcohol per 1.5 fluid oz serving and 0g of carbohydrates.
• A pint of beer contains 500 mmol of alcohol or 2 units.
• 1/5 gill of whisky contains 250 mmol of alcohol or 1 unit.
• A glass of sherry contains 325 mmol of alcohol or 1 unit.
• 1 glass of wine contains 200 mmol of alcohol or 1 unit.
• Clinically, 1 unit represents 8g of pure alcohol.

Alcohol Absorption, Transportation, and Excretion

• Alcohol is rapidly absorbed via simple diffusion along the entire GI tract; approximately 20% is absorbed in the stomach.
• Once absorbed, alcohol is quickly distributed throughout all body water compartments.
• Roughly 90% of alcohol is metabolized by the liver.
• 5% of alcohol is excreted in urine.
• The remainder of alcohol is eliminated through the lungs.

Factors Affecting Blood Alcohol Level

• Weight: The more a person weighs, the more body water they have, which results in greater dilution of alcohol in their blood after the same consumption.
• Gender: Men generally have lower blood alcohol levels compared to women of the same size after consuming the same amount of alcohol because men have more body water and more stomach ADH (alcohol dehydrogenase).
• The more food eaten before drinking, the slower the alcohol absorption, resulting in a lower blood alcohol content.
• The body metabolizes alcohol slowly, so blood alcohol level rises with the number of drinks consumed per hour.
• Drink Type: The amount of alcohol in the consumed drink affects how fast blood alcohol levels increase, carbonated mixers cause quicker alcohol absorption.

Alcohol (Ethanol) Metabolism Pathways

• Cytosol alcohol dehydrogenase (ADH) breaks down small amounts of alcohol.
• The microsomal ethanol-oxidizing system (MEOS) is important for breaking down large amounts of alcohol and processes xenobiotics.
• Colon bacterial ADH metabolizes alcohol to acetaldehyde, a toxic compound.

Metabolic Route of Ethanol

• In the liver, ADH converts ethanol to acetaldehyde, and ALDH converts acetaldehyde to acetate.
• Acetate can then go into the blood to the muscles.
• In the muscle, ACS converts acetate to Acetyl CoA, which goes into the TCA cycle.
• During ethanol consumption, the metabolism of ethanol results in a large increase in cytosolic NADH in the liver.
• The ethanol-mediated increase in NADH causes the intermediates of gluconeogenesis to be diverted into alternate reaction pathways, resulting in decreased synthesis of glucose.
• Fomepizole blocks alcohol dehydrogenase and is the preferred antidote for methanol or ethylene glycol overdoses related to attempted or successful suicide.
• Alcohol dehydrogenase has a higher affinity for ethanol than for methanol or ethylene glycol.
• Ethanol can be used as a competitive inhibitor of alcohol dehydrogenase to treat methanol or ethylene or ethylene glycol poisoning.

Alcohol Metabolism - High vs. Low Doses

• At high doses of alcohol, MEOS is used in the mitochondria and endoplasmic reticulum.
• At low doses of alcohol Alcohol dehydrogenase is used.
• Both result in Acetaldehyde.
• Acetaldehyde converted to Acetyl- CoA by Aldehyde dehydrogenase.
• Leads to increased fatty acids.
• High does of alcohol reduces the Citric Acid Cycle.
• The MEOS system is comprised of lots of different cytochromes.
• The MEOS system has specifictiy that is not absolute.
• The MEOS system has ability to process other substances but the same system is impaired

Alcohol Dehydrogenase (ADH)

• ADH, for relatively low dose alcohol
• Family of isoenzymes
• ADH with highest specificity for EtOH – class 1 ADHs
• Three genes exist for class 1 ADH, where each exists as allelic variants (polymorphisms).
• Class 1 ADH is high in the liver, accounting for 3% of the soluble protein
• Class 1 ADH has low Km (high affinity) for alcohol indicating the liver is the major EtOH metabolism site and the major site for generation of toxic acetaldehyde.
• ADH(class iv) is also in the GIT – acetaldehyde generated here may contribute to cancers of this system
• ADH (Class 11) primarily expressed in the liver and at a lower level in the lower Gl tract
• ADH 1A and ADH 1C are functional polymorphisms.
• Differences in ethanol elimination rates among individuals or populations are partially caused by ADH 1A and ADH 1C functional polymorphisms.
• Possession of the ADH1B*2 allele (which encodes a relatively fast ADH) associates with decreased susceptibility to alcoholism, which results in Nausea and flushing caused by acetaldehyde accumulation because ALDH cannot processes the increased acetaldehyde from ADH fast enough
• This allele is high frequency in East Asian populations and low frequency in white Europeans.

Acetaldehyde DH (ALDH)

• 80% of acetaldehyde is processed by mitochondrial acetaldehyde DH (ALDH2).
• ALDH2 has high affinity for acetaldehyde and is very specific.
• Individuals with an allelic variant of ALDH2 have a greatly decreased capacity for acetaldehyde metabolism.
• ALDH1 is cytosolic.
• Accumulation of acetylaldehyde results in nausea and vomiting.
• Inactive variants of ALDH associated with protection against alcoholism.
• Drug treatment for alcoholism often includes an ALDH inhibitor.

Fate of Acetate

• Metabolism of acetate requires activation to acetyl CoA.
• Liver – ACS1 generates acetyl CoA for the cytosolic synthesis of cholesterol and FA.
• Most acetate enters the blood.
• Taken up by heart and skeletal muscle (high conc of ACS11).
• Acetyl CoA that can enter TCA cycle and is oxidized.

Microsomal Ethanol Oxidizing System (MEOS)

• Comprises members of cytochrome P450 superfamily of enzymes.
• Within the superfamily in mammals are 10 distinct gene families.
• Over 100 cyt P450 isoenzymes exist within 10 gene families.
• MEOS refers to the combined ethanol oxidizing activity of all P450 enzymes.
• CYP2E1 has a higher Km for ethanol than class 1 ADHs.
• A greater proportion of ethanol is metabolized through CYP2E1 at high levels of EtOH consumption than at low levels.
• Chronic consumption increases hepatic CYP2E1 levels 5-10 fold and increases other P450s.
• ER proliferates.
• P450 enzymes generate free radicals, which results in hepatic injury.
• Overlapping specificities, which results in drug interactions.

E.g. Phenobarbital interaction (CYP2B2) –ethanol is an inhibitor.

Acute Effects of Ethanol Metabolism

• High NADH/NAD+ Ratio- inhibits the oxidation of FAs, FA accumulate in the liver and form TAGs
• Promotes synthesis of glycerol 3-P from glycolysis intermediates.
• TAGs incorporated into VLDLs that accumulate in liver and enter the blood, which results in ethanol-induced hyperlipidemia.
• Alcohol-induced Ketoacidosis, FAs are oxidized to acetyl-CoA and then to ketone bodies.
• OAA converted to Malate in TCA, leaving OAA levels are too low for citrate synthase to synthesize citrate.
• Ketone bodies are produced at a high rate that might be much higher than found under normal fasting conditions.
• Lactic acidosis, hyperuricemia and hypoglycemia are also effects ethanol consumption
• The balance of LDH is shifted toward lactate, resulting in lactate acidosis.
• Uric acid excretion by kidneys is potentially decreased
• Patients with gout advised not to consume excessive amounts of ethanol.
• Hypoglycemia occurs in fasting individuals because they are dependent on gluconeogenesis, which is affected by ethanol, to maintain blood glucose, and lactate and alanine (major gluconeogenesis precursors) that enter as pyruvate can not enter gluconeogenesis as likely.
• Ethanol consumption with a meal results in transient hyperglycemia because of the inhibition of glycolysis.

Acetaldehyde Toxicity

• Many of the toxic effects of chronic ethanol consumption result from an accumulation of acetaldehyde produced from EtOH by both ADHs and MEOS.
• Acetaldehyde accumulates in the liver and is released into the blood after EtOH consumption.
• Acetaldehyde is highly reactive and binds covalently to amino acids, sulfhydryl groups, nucleotides and phospholipids to form adducts.

Acetaldehyde and Alcohol-Induced Hepatitis

• Acetaldehyde-adduct formation with amino acids results in a decrease in hepatic protein synthesis.
• Proteins in the heart are also affected.
• Tubulin synthesis is decreased, resulting in diminished secretion of serum proteins and VLDL from the liver.
• Proteins accumulate in liver along with lipid.
• Accumulation of protein leads to influx of water in hepatocytes.
• Liver swells, which contributes to portal hypertension and disruption of liver architecture.
• Acetaldehyde adduct formation causes free radical damage.
• Acetaldehyde binds directly to glutathione, which decreases its ability to protect against H2O2 and prevent lipid peroxidation.
• Mitochondrial damage leads to a cycle of toxicity.
• ETC is inhibited, ox phos decoupled, and decreased ATP.
• FA oxidation is decreased, which leads to lipids accumulation.
• Increased oxidative stress in the liver comes from increased production of free radicals principally by CYP2E1.
• FAD and FMN in the reductase and heme in the cyt P450 system transfer single electrons and thus operate through a mechanism that can generate free radicals.
• Induction of all P450s can increase generation of free radicals from drug met and toxins/carcinogens etc.
• Phospholipids are the primary target of peroxidation caused by free radical release.

Hepatic Cirrhosis and Loss of Liver Function

• Liver injury is irreversible at the stage that hepatic cirrhosis develops.
• Liver becomes enlarged, full of fat, and crossed with collagen fibers.
• Laennec's cirrhosis (liver shrunken)
• Normal metabolic processes are negatively affected.

Alcoholism & Fatty Liver

• NADH levels in the liver are elevated.
• High levels of NADH 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 frequently associated with chronic alcoholism.
• When alcohol-induced liver disease progresses, the ability to secrete the TAGs diminishes, resulting in a fatty liver.

Physiological Impact of Alcohol

• Gender differences exist because women have lower activity of stomach ADH and less body water than men.
• Products of alcohol metabolism by ADH promote fat synthesis.
• Reactive oxygen molecules are generated in MEOS pathway.

Adverse Effects of Alcohol Consumption

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

Alcoholic drinks contain water, ethanol, and sugar. Energy, carbs, and alcohol content vary per beverage. For example, Long Island iced tea (7 fl oz) contains 170 kcal, 24.3g carbs, and 17.8g alcohol, while a light beer (12 fl oz) typically contains 100 kcals, 4.6g carbs and 11.3g alcohol.