Alcohol Metabolism

Most toxicologists consider ethanol to be the most often used and abused chemical substance Most toxicologists consider ethanol to be the most often used and abused chemical substance The measurement of ethanol is one of the more frequently performed tests in the toxicology laboratory The measurement of ethanol is one of the more frequently performed tests in the toxicology laboratory When alcohol consumed with other CNS depressant drugs, ethanol exerts a potentiation or synergistic depressant effect When alcohol consumed with other CNS depressant drugs, ethanol exerts a potentiation or synergistic depressant effect Ethanol absorbed to a small extent in the stomach and mainly by the upper small intestine Ethanol absorbed to a small extent in the stomach and mainly by the upper small intestine After the consumption of alcohol blood alcohol concentration peaks within 30 to 45 minutes After the consumption of alcohol blood alcohol concentration peaks within 30 to 45 minutes

Alcohol cannot be stored and has priority in metabolism Alcohol cannot be stored and has priority in metabolism Through oxidation, alcohol is detoxified and removed from the blood, preventing the alcohol from accumulation and destroying cells and organs Through oxidation, alcohol is detoxified and removed from the blood, preventing the alcohol from accumulation and destroying cells and organs Some ethanol are metabolized by the stomach cells Some ethanol are metabolized by the stomach cells Most of the alcohol consumed is metabolized in the liver, but the small quantity that remains unmetabolized permits alcohol concentration to be measured in breath and urine Most of the alcohol consumed is metabolized in the liver, but the small quantity that remains unmetabolized permits alcohol 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

Effect»mMmg% released from inhibitions and restraints, some impairment of judgment 1050 motor function impaired motor function markedly depressed sensory perception is lost; stuporous, but still conscious comatose respiration ceases ® death

Factors Influencing Alcohol Absorption and Metabolism Food: Food: – The presence of food – Type of food Gender: Gender: – Females are more susceptible to alcohol toxicity than males

Conversion of ethanol to acetaldehyde Catalyzed by alcohol dehydrogenase IB a member of the alcohol dehydrogenase family Catalyzed by alcohol dehydrogenase IB a member of the alcohol dehydrogenase family Consisting of several homo- and heterodimers of alpha, beta and gamma subunits Consisting of several homo- and heterodimers of alpha, beta and gamma subunits The rate-determining reaction in ethanol metabolism The rate-determining reaction in ethanol metabolism This family of enzymes metabolize a wide variety of substrates This family of enzymes metabolize a wide variety of substrates – Ethanol – Retinol – Hydroxysteroids – Lipid peroxidation products – Other aliphatic alcohols

ADH 5 different isoforms are present ADH 1 to ADH 5. 5 different isoforms are present ADH 1 to ADH 5. The ADH 2 isoform is commonly called ‘atypical’ ADH. The ADH 2 isoform is commonly called ‘atypical’ ADH. – This isoform contains a variant beta 2 subunit instead of the usual beta 1 subunit. beta 2 has much higher activity than beta 1.

Conversion of acetaldehyde to acetic acid The enzyme responsible for this conversion is aldehyde dehydrogenase II, this enzyme belongs to the aldehyde dehydrogenase family of protiens The enzyme responsible for this conversion is aldehyde dehydrogenase II, this enzyme belongs to the aldehyde dehydrogenase family of protiens – Two major liver isoforms of this enzyme: Cytosolic Cytosolic Mitochondrial Mitochondrial – These two isoforms can be distinguished by their: Electrophoretic mobilities Electrophoretic mobilities Kinetic properties Kinetic properties Sub-celellular localizations Sub-celellular localizations

Acetaldehyde Far more toxic than ethanol. Far more toxic than ethanol. Acetaldehyde is a highly unstable compound and quickly forms free radical structures Acetaldehyde is a highly unstable compound and quickly forms free radical structures The injury ; from fatty infiltration to fibrosis and if the hepatocellular necrosis and liver insult continue, cirrhosis and even death. The injury ; from fatty infiltration to fibrosis and if the hepatocellular necrosis and liver insult continue, cirrhosis 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 metabolize acetaldehyde and NOT ethanol. Alcohol sensitivity symptoms is all due to the inability to metabolize acetaldehyde and NOT ethanol.

Metabolic fates of NADH Conversion of pyruvic acid to lactic acid: Conversion of pyruvic acid to lactic acid: – Lactic acid build-up; Acidosis – Lack of glucose synthesis; Hypoglycemia Synthesis of lipids: Synthesis of lipids: – Synthesis of glycerol – Synthesis of fatty acids Electron transport chain: Electron transport chain: – ATP synthesis – Fats accumulation – Acetyl CoA accumulation with ketone bodies formation

Microsomal ethanol oxidizing system (MEOS) Excessive alcohol intake, ADH cannot keep up with demand Excessive alcohol intake, ADH cannot keep up with demand Used to metabolize drugs, foreign substances in addition to alcohol Used to metabolize drugs, foreign substances in addition to alcohol Involving cytochrome P450 especially CYP2E1 Involving cytochrome P450 especially CYP2E1 CYP1A2 and CYP3A4 are also involved CYP1A2 and CYP3A4 are also involved Chronic ethanol consumption increases the activity of MEOS including CYP2E1 Chronic ethanol consumption increases the activity of MEOS including CYP2E1 CYP2E1 activates CYP2E1 activates – Catabolism of acetaminophen to their toxic metabolites – Accelerates catabolism of retinol resulting in its depletion – Significant release of free radicals, diminishes reduced glutathione (GSH)

CO 2 + H 2 O Acetyl-CoA Fatty Acid X Glucose Fate of Acetyl-CoA

Effects of alcohol metabolism Body weight: drinkers were not more obese than nondrinkers Body weight: drinkers were not more obese than nondrinkers Sex hormones: alcohol metabolism alters the balance of reproductive hormones in men (impairs testosterone synthesis and sperm production) and women (increase production of estradiol) Sex hormones: alcohol metabolism alters the balance of reproductive hormones in men (impairs testosterone synthesis and sperm production) and women (increase production of estradiol) Medications: activation the enzyme CYP2E1, which may be responsible for the transformation of many drugs into chemicals that can cause liver damage Medications: activation the enzyme CYP2E1, which may be responsible for the transformation of many drugs into chemicals that can cause liver damage

Why some people develop alcoholism and others do not??? Why some people develop alcoholism and others do not??? – Alcohol dehydrogenase genes may be associated with differential resistance and vulnerability to alcohol – Alternate paths of alcohol metabolism

Negative Effects of Ethanol

Oxidation of alcohol takes precedence over other metabolic pathways Oxidation of alcohol takes precedence over other metabolic pathways Elevated NADH + H +, which favors rx’s which require NADH + H + Elevated NADH + H +, which favors rx’s which require NADH + H + Synthesis of glycerol-PO 4 Synthesis of glycerol-PO 4 pyruvate > lactate pyruvate > lactate acetyl-CoA-----> citrate-----> fatty acids acetyl-CoA-----> citrate-----> fatty acids Fatty infiltration of liver due to excessive alcohol consumption: Fatty infiltration of liver due to excessive alcohol consumption: 1) Decrease fat oxidation 2) Increase lipogenesis 3) Decrease lipoprotein release

 Proteins: 1) Inhibit protein synthesis in brain 2) High concentration of ethanol can inhibit the absorption of some amino acids.  Isoleucine,  Arginine, and  Methionine  Micronutrients: 1) Poor intake 2) Changes in  Absorption  Storage  Metabolism  Excretion

Folate deficiency due to: Folate deficiency due to: 1) Decrease absorption 2) Decrease hepatic uptake or storage 3) Increase urinary excretion -Leading cause of anemia in alcoholics Thiamin: Thiamin: – impaired intestinal absorption Pyridoxine (B6): Pyridoxine (B6): 1) Decrease hepatic stores 2) Increase urinary loss

Vitamin A: Vitamin A: 1) Decrease hepatic storage, especially with cirrhosis 2) Possible increase in vitamin A metabolism in microsomes, causing increase retinoic acid 3) Malabsorption as a fat-soluble vitamin -Decrease in cellular differentiation which promotes tumor growth Zinc: Zinc: 2) Impaired absorption 3) Increase urinary excretion Selenium and Vitamin E: Selenium and Vitamin E: 1) Slight decrease in plasma concentration

Damage to the GI Tract Damage the cells, inflammation of the stomach, oesophagus, and intestines Damage the cells, inflammation of the stomach, oesophagus, and intestines – Malabsorption – Diarrhea and steatorrhea Inflammation of the pancreas and gall bladder Inflammation of the pancreas and gall bladder – Decrease enzyme production – Disturbance in bile excretion Difficulty digesting (and absorbing) nutrients Difficulty digesting (and absorbing) nutrients

Cardiovascular Disease (CVD) Moderate consumption of alcohol can increase HDL levels, which can reduce the risk of CVD ?? Moderate consumption of alcohol can increase HDL levels, which can reduce the risk of CVD ?? HDL protects against the deposition of arterial fatty plaque HDL protects against the deposition of arterial fatty plaque

Cirrhosis Fatty infiltration of the liver Fatty infiltration of the liver Response to increased synthesis of fat from accelerated acetyl-CoA production Response to increased synthesis of fat from accelerated acetyl-CoA production Enlarge fat cells chokes off nutrients and O 2 supply to liver cells Enlarge fat cells chokes off nutrients and O 2 supply to liver cells Engorged fat cells burst and die Engorged fat cells burst and die Scar tissue Scar tissue 50% chance of death within 4 years 50% chance of death within 4 years

Brain Damage Cognitive dysfunction and motor nerve deficit Cognitive dysfunction and motor nerve deficit Shrinks the brain Shrinks the brain Reduces oxygen and nutrients to the brain Reduces oxygen and nutrients to the brain Alcohol is a powerful depressant Alcohol is a powerful depressant