Alcohol MetabolismAlcohol Metabolism

• Most toxicologists consider ethanol to be the most Most toxicologists consider ethanol to be the most often used and abused chemical substanceoften used and abused chemical substance

• The measurement of ethanol is one of the more The measurement of ethanol is one of the more frequently performed tests in the toxicology frequently performed tests in the toxicology laboratorylaboratory

• When alcohol consumed with other CNS When alcohol consumed with other CNS depressant drugs, ethanol exerts a potentiation or depressant drugs, ethanol exerts a potentiation or synergistic depressant effectsynergistic depressant effect

• Ethanol absorbed to a small extent in the stomach Ethanol absorbed to a small extent in the stomach and mainly by the upper small intestineand mainly by the upper small intestine

• After the consumption of alcohol blood alcohol After the consumption of alcohol blood alcohol concentration peaks within 30 to 45 minutesconcentration peaks within 30 to 45 minutes

• Alcohol cannot be stored and has priority in metabolismAlcohol cannot be stored and has priority in metabolism

• Through oxidation, alcohol is detoxified and removed from Through oxidation, alcohol is detoxified and removed from the blood, preventing the alcohol from accumulation and the blood, preventing the alcohol from accumulation and destroying cells and organsdestroying cells and organs

• Some ethanol are metabolized by the stomach cellsSome ethanol are metabolized by the stomach cells

• Most of the alcohol consumed is metabolized in the liver, Most of the alcohol consumed is metabolized in the liver, but the small quantity that remains unmetabolized permits but the small quantity that remains unmetabolized permits alcohol concentration to be measured in breath and urinealcohol concentration to be measured in breath and urine

• Alcohol is metabolized more slowly than it is absorbed Alcohol is metabolized more slowly than it is absorbed

mgmg%%»»mMmMEffectEffect

50501010released from inhibitions and released from inhibitions and restraints, some impairment of restraints, some impairment of judgmentjudgment

1001002020motor function impairedmotor function impaired

2002004040motor function markedly depressedmotor function markedly depressed

3003006060sensory perception is lost; stuporous, sensory perception is lost; stuporous, but still consciousbut still conscious

400-500400-500100100comatosecomatose

700700100100respiration ceases ® deathrespiration ceases ® death

Factors Influencing Alcohol Absorption and Factors Influencing Alcohol Absorption and MetabolismMetabolism

• Food:Food:– The presence of food The presence of food

– Type of foodType of food

• Gender:Gender:– Females are more susceptible to alcohol toxicity than Females are more susceptible to alcohol toxicity than

malesmales

Conversion of ethanol to acetaldehyde Conversion of ethanol to acetaldehyde

• Catalyzed by alcohol dehydrogenase IB a member of the Catalyzed by alcohol dehydrogenase IB a member of the alcohol dehydrogenase familyalcohol dehydrogenase family

• Consisting of several homo- and heterodimers of alpha, Consisting of several homo- and heterodimers of alpha, beta and gamma subunitsbeta and gamma subunits

• The rate-determining reaction in ethanol metabolismThe rate-determining reaction in ethanol metabolism• This family of enzymes metabolize a wide variety of This family of enzymes metabolize a wide variety of

substratessubstrates– EthanolEthanol– RetinolRetinol– HydroxysteroidsHydroxysteroids– Lipid peroxidation productsLipid peroxidation products– Other aliphatic alcoholsOther aliphatic alcohols

ADHADH

• 5 different isoforms are present ADH5 different isoforms are present ADH11 to ADH to ADH55..

• The ADHThe ADH22 isoform is commonly called ‘atypical’ ADH. isoform is commonly called ‘atypical’ ADH.

– This isoform contains a variant This isoform contains a variant betabeta22 subunit instead of subunit instead of

the usual the usual betabeta11 subunit. subunit. betabeta22 has much higher activity has much higher activity

than than betabeta11..

Conversion of acetaldehyde to acetic acidConversion of acetaldehyde to acetic acid• The enzyme responsible for this conversion is The enzyme responsible for this conversion is

aldehyde dehydrogenase II, this enzyme belongs to aldehyde dehydrogenase II, this enzyme belongs to the aldehyde dehydrogenase family of protiensthe aldehyde dehydrogenase family of protiens– Two major liver isoforms of this enzyme:Two major liver isoforms of this enzyme:

• CytosolicCytosolic• MitochondrialMitochondrial

– These two isoforms can be distinguished by These two isoforms can be distinguished by their:their:• Electrophoretic mobilitiesElectrophoretic mobilities• Kinetic propertiesKinetic properties• Sub-celellular localizationsSub-celellular localizations

AcetaldehydeAcetaldehyde

• Far more toxic than ethanol.Far more toxic than ethanol.

• Acetaldehyde is a highly unstable compound and quickly Acetaldehyde is a highly unstable compound and quickly forms free radical structuresforms free radical structures

• The injury ; from fatty infiltration to fibrosis and if the The injury ; from fatty infiltration to fibrosis and if the hepatocellular necrosis and liver insult continue, cirrhosis hepatocellular necrosis and liver insult continue, cirrhosis and even death. and even death.

• The fibrosis and cirrhosis are irreversible.The fibrosis and cirrhosis are irreversible.

• Alcohol sensitivity symptoms is all due to the inability to Alcohol sensitivity symptoms is all due to the inability to metabolize acetaldehyde and NOT ethanolmetabolize acetaldehyde and NOT ethanol..

Metabolic fates of NADHMetabolic fates of NADH

• Conversion of pyruvic acid to lactic acid:Conversion of pyruvic acid to lactic acid:– Lactic acid build-up; AcidosisLactic acid build-up; Acidosis– Lack of glucose synthesis;Lack of glucose synthesis; HypoglycemiaHypoglycemia

• Synthesis of lipids:Synthesis of lipids:– Synthesis of glycerolSynthesis of glycerol– Synthesis of fatty acidsSynthesis of fatty acids

• Electron transport chain:Electron transport chain:– ATP synthesisATP synthesis– Fats accumulationFats accumulation– Acetyl CoA accumulation with ketone bodies formationAcetyl CoA accumulation with ketone bodies formation

Microsomal ethanolMicrosomal ethanol oxidizing system (MEOS)oxidizing system (MEOS) • Excessive alcohol intake, ADH cannot keep up with demandExcessive alcohol intake, ADH cannot keep up with demand

• Used to metabolize drugs, foreign substances in addition to alcoholUsed to metabolize drugs, foreign substances in addition to alcohol

• Involving cytochrome P450 especially CYP2E1Involving cytochrome P450 especially CYP2E1

• CYP1A2 and CYP3A4 are also involvedCYP1A2 and CYP3A4 are also involved

• Chronic ethanol consumption increases the activity of MEOS Chronic ethanol consumption increases the activity of MEOS including CYP2E1including CYP2E1

• CYP2E1 activatesCYP2E1 activates– Catabolism of acetaminophen to their toxic metabolitesCatabolism of acetaminophen to their toxic metabolites– Accelerates catabolism of retinol resulting in its depletionAccelerates catabolism of retinol resulting in its depletion– Significant release of free radicals, diminishes reduced glutathione (GSH)Significant release of free radicals, diminishes reduced glutathione (GSH)

CO2 + H2O

Acetyl-CoA Fatty Acid X

Glucose

Fate of Acetyl-CoA

Effects of alcohol metabolismEffects of alcohol metabolism

• Body weight: drinkers were not more obese than Body weight: drinkers were not more obese than nondrinkersnondrinkers

• Sex hormones: alcohol metabolism alters the balance of Sex hormones: alcohol metabolism alters the balance of reproductive hormones in men (impairs testosterone reproductive hormones in men (impairs testosterone synthesis and sperm production) and women (increase synthesis and sperm production) and women (increase production of estradiol)production of estradiol)

• Medications: activation the enzyme CYP2E1, which may Medications: activation the enzyme CYP2E1, which may be responsible for the transformation of many drugs into be responsible for the transformation of many drugs into chemicals that can cause liver damage chemicals that can cause liver damage

• Why some people develop alcoholism and others Why some people develop alcoholism and others do not???do not???

– Alcohol dehydrogenase genes may be associated Alcohol dehydrogenase genes may be associated with differential resistance and vulnerability to with differential resistance and vulnerability to alcoholalcohol

– Alternate paths of alcohol metabolismAlternate paths of alcohol metabolism

Negative Effects of EthanolNegative Effects of Ethanol

• Oxidation of alcohol takes precedence over other metabolic Oxidation of alcohol takes precedence over other metabolic pathwayspathways

• Elevated NADH + HElevated NADH + H++, which favors rx’s which require , which favors rx’s which require NADH + HNADH + H++

• Synthesis of glycerol-POSynthesis of glycerol-PO44

• pyruvate ------> lactatepyruvate ------> lactate• acetyl-CoA-----> citrate-----> fatty acidsacetyl-CoA-----> citrate-----> fatty acids

• Fatty infiltration of liver due to excessive alcohol Fatty infiltration of liver due to excessive alcohol consumption:consumption:1) Decrease fat oxidation1) Decrease fat oxidation2) Increase lipogenesis2) Increase lipogenesis3) Decrease lipoprotein release3) Decrease lipoprotein release

Proteins:Proteins:1) Inhibit protein synthesis in brain1) Inhibit protein synthesis in brain2) High concentration of ethanol can inhibit the absorption of some amino 2) High concentration of ethanol can inhibit the absorption of some amino

acids.acids.Isoleucine, Isoleucine, Arginine, and Arginine, and MethionineMethionine

Micronutrients:Micronutrients:1) Poor intake1) Poor intake2) Changes in 2) Changes in

AbsorptionAbsorptionStorageStorageMetabolismMetabolismExcretionExcretion

• Folate deficiency due to:Folate deficiency due to:

1) Decrease absorption1) Decrease absorption

2) Decrease hepatic uptake or storage2) Decrease hepatic uptake or storage

3) Increase urinary excretion3) Increase urinary excretion

-Leading cause of anemia in alcoholics-Leading cause of anemia in alcoholics

• Thiamin:Thiamin:

– impaired intestinal absorptionimpaired intestinal absorption

• • Pyridoxine (B6):Pyridoxine (B6):

1) Decrease hepatic stores1) Decrease hepatic stores

2) Increase urinary loss2) Increase urinary loss

• Vitamin A:Vitamin A:1) Decrease hepatic storage, especially with cirrhosis1) Decrease hepatic storage, especially with cirrhosis2) Possible increase in vitamin A metabolism in 2) Possible increase in vitamin A metabolism in

microsomes, causing increase retinoic acidmicrosomes, causing increase retinoic acid3) Malabsorption as a fat-soluble vitamin3) Malabsorption as a fat-soluble vitamin

-Decrease in cellular differentiation which -Decrease in cellular differentiation which promotes tumor growthpromotes tumor growth

• • Zinc:Zinc:

2) Impaired absorption2) Impaired absorption3) Increase urinary excretion3) Increase urinary excretion

• Selenium and Vitamin ESelenium and Vitamin E::1) Slight decrease in plasma concentration1) Slight decrease in plasma concentration

Damage to the GI TractDamage to the GI Tract

• Damage the cells, inflammation of the stomach, Damage the cells, inflammation of the stomach, oesophagus, and intestinesoesophagus, and intestines– MalabsorptionMalabsorption– Diarrhea and steatorrheaDiarrhea and steatorrhea

• Inflammation of the pancreas and gall bladderInflammation of the pancreas and gall bladder– – Decrease enzyme productionDecrease enzyme production– – Disturbance in bile excretionDisturbance in bile excretion Difficulty digesting (and absorbing) nutrientsDifficulty digesting (and absorbing) nutrients

Cardiovascular Disease (CVD)Cardiovascular Disease (CVD)

• Moderate consumption of alcohol can increase HDL levels, Moderate consumption of alcohol can increase HDL levels, which can reduce the risk of CVD which can reduce the risk of CVD ????

• HDL protects against the deposition of arterial fatty HDL protects against the deposition of arterial fatty plaqueplaque

CirrhosisCirrhosis

• Fatty infiltration of the liverFatty infiltration of the liver• Response to increased synthesis of fat from accelerated Response to increased synthesis of fat from accelerated

acetyl-CoA productionacetyl-CoA production

• Enlarge fat cells chokes off nutrients and OEnlarge fat cells chokes off nutrients and O22 supply to liver supply to liver cellscells

• Engorged fat cells burst and dieEngorged fat cells burst and die• Scar tissueScar tissue• 50% chance of death within 4 years50% chance of death within 4 years

Brain DamageBrain Damage

• Cognitive dysfunction and motor nerve deficitCognitive dysfunction and motor nerve deficit

• Shrinks the brainShrinks the brain

• Reduces oxygen and nutrients to the brainReduces oxygen and nutrients to the brain

• Alcohol is a powerful depressantAlcohol is a powerful depressant