Alcohol Metabolism 2023-2024 PDF

Alcohol Metabolism Feb 2024 What’s in Alcoholic Beverages? Alcoholic beverages consist primarily of water, ethanol, and sugar. Clinical purposes – 1 unit represents 8g of pure alcohol Absorption, Transportation, and Excretion of Alcohol Alcohol is rapidly absorbed by simple diffusion along the entir...

Alcohol Metabolism Feb 2024 What’s in Alcoholic Beverages? Alcoholic beverages consist primarily of water, ethanol, and sugar. Clinical purposes – 1 unit represents 8g of pure alcohol Absorption, Transportation, and Excretion of Alcohol Alcohol is rapidly absorbed by simple diffusion along the entire GI tract. About 20% is absorbed in the stomach Absorbed alcohol is rapidly distributed throughout all body water compartments. About 90% of the alcohol is metabolized by the liver, 5% is excreted into the urine, and the remainder is eliminated via the lungs. Factors Affecting Blood Alcohol Level Alcohol (Ethanol) Metabolism Two Primary Pathways – Cytosol alcohol dehydrogenase (ADH): for breaking down small amounts of alcohol – Microsomal ethanol-oxidizing system (MEOS): important for breaking down large amounts of alcohol Alcohol is also metabolized by colon bacterial ADH to yield acetaldehyde—a toxic compound. Major route for metabolism of ethanol and use of acetate by the muscle Fomepizole Fomepizole – blocks alcohol dehydrogenase, preferred antidote for overdoses of methanol or ethylene glycol Alcohol dehydrogenase has affinity for ethanol than for methanol or ethylene glycol Ethanol can be used as competitive inhibitor of alcohol dehydrogenase to treat methanol or ethylene or ethylene glycol poisoning Two Primary Pathways of Alcohol Metabolism F1-7 Alcohol Dehydrogenase Family of isoenzymes ADH with highest specificity for EtOH – class 1 ADHs 3 genes for class 1 ADH – each exists as allelic variants (polymorphisms) Class 1 – high in liver- 3% of the soluble protein low Km/high affinity for alcohol Liver thus major site of EtOH metabolism and the major site for generation of toxic acetaldehyde ADH(class iv) 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 GI tract Functional Polymorphisms ADH 1A and ADH 1C – functional polymorphisms Can partially account for observed differences in ethanol elimination rates among individuals or population Possession of ADH1B*2 allele (which encodes a relatively fast ADH) is associated with decreased susceptibility to alcoholism –nausea and flushing caused by acetaldehyde accumulation – ALDH cannot keep up with ADH This allele high frequency in East Asian population and low frequency in white Europeans Acetaldehyde DH (ALDH) 80% by mitochondrial acetaldehyde DH (ALDH2) Enzyme has high affinity for acetaldehyde and is very specific Individuals with a allelic variant of ALDH2 have a greatly decreased capacity for acetaldehyde metabolism ALDH1 – cytosolic Accumulation of acetylaldehyde causes nausea and vomiting Inactive variants of ALDH associated with protection against alcoholism Drug treatment for alcoholism –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) Generates acetyl CoA that can enter TCA cycle oxidized Microsomal Ethanol Oxidizing System (MEOS) Comprises members of cytochrome P450 superfamily of enzymes Within the superfamily in mammals are 10 distinct gene families > 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 Greater proportion of ethanol is metabolized through CYP2E1 at high levels of EtOH consumption than at low levels Induction of P450 enzymes Chronic consumption increases hepatic CYP2E1 levels 5-10 fold Also  other P450s ER proliferates P450 enzymes generate free radicals – hepatic injury Overlapping specificities- drug interactionsmajor consequences E.g. Phenobarbital interaction (CYP2B2) –ethanol is an inhibitor Acute effects of ethanol metabolism arising from the increased NADH/NAD+ Ratio 1. Changes in FA metabolism high ratio inhibits the oxidation of FAsaccumulate in liver – form TAGs Promotes synthesis of glycerol 3-P from glycolysis intermediates TAGs incorporated into VLDLs that accumulate in liver and enter the blood resulting in ethanol-induced hyperlipidemia 2. Alcohol-induced Ketoacidosis FAs oxidized to acetyl-CoA and then to ketone bodies OAA to Malate in TCA , leaves OAA levels too low for citrate synthase to synthesize citrate Ketone bodies are produced at a high rate – conc here might be much higher than found under normal fasting conditions Acute effects of ethanol arising from the increased NADH/NAD+ Ratio -3 3. Lactic acidosis, hyperuricemia and hypoglycemia – Balance of LDH is shifted toward lactate – resulting in lactate acidosis – This may decrease excretion of uric acid by kidneys (patients with gout advised not to consume excessive amounts of ethanol) – Hypoglycemia – in fasting individual who has been drinking – therefore dependent on gluconeogenesis to maintain blood glucose – Lactate and alanine – major gluconeogenesis precursors enter as pyruvate. Ratio shifts towards lactate and therefore cannot enter – Ethanol consumption with meal – transient hyperglycemia – due to 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 Accumulates in the liver and is released into the blood after EtOH consumption 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 Aas – result – decrease in hepatic protein synthesis Proteins in the heart also affected Decrease in tubulin synthesis – diminished secretion of serum proteins and VLDL from liver Proteins accumulate in liver along with lipid Accumulation of protein leads to influx of water in hepatocytes Liver swells - contributes to portal hypertension and disruption of liver architecture - Acetaldehyde and Free Radical Damage Acetaldehyde adduct formation causes free radical damage Binds directly to glutathione and diminishes its ability to protect against H2O2 and prevent lipid peroxidation Mitochondrial damage –cycle of toxicity ( 3 and 4 –diagram) ETC inhibited, ox phos uncoupled FA oxidation further decreased – lipids accumulation (5) Ethanol and Free Radical Formation Increased oxidative stress in the liver arises 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-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 – 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 – enlarged, full of fat, crossed with collagen fibers Laennec’s cirrhosis (liver shrunken) Normal metabolic processes lost Alcoholism & Fatty Liver NADH levels in the liver are elevated High levels of NADH inhibit the oxidation of fatty acids Therefore, 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 is diminished – resulting in a fatty liver Physiological Impact of Alcohol Metabolism Gender difference – 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. Physiological Impact of Alcohol Metabolism F1-9 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. Acute Effects of Alcohol Consumption When alcohol intake exceeds the ability of the liver to break it down, alcohol intoxication or alcohol poisoning can occur. The circulating alcohol affects the central nervous system, breathing, and heart rate. Acute Effects of Alcohol Consumption Blood conc (mg/dl) SYMPTOMS < 50 Dry & Decent 50-150 Dizzy & Devilish 150-250 Delirious 250-350 Dazed & Dejected 350-500 Dead drunk >500 Dead! Normal liver Chronic alcohol consumption causes permanent liver damage Cirrhotic liver Sample MCQs Which of the following statements is true a) Class 1 ADHs have a low Km for ethanol b) Class 1 ADHs have the lowest specificity for EtOH c) CYP2E1 has a lower Km for ethanol than class 1 ADHs d) Chronic alcohol consumption suppresses P450 enzyme systems e) Acute effects of ethanol arise from the increased NAD+/NADH ratio Which of the following would be expected to occur after alcohol ingestion? The activation of FAO Lactic acidosis The inhibition of ketogenesis + An increase in the NAD /NADH An increase in gluconeogenesis A chronic alcoholic is in treatment for alcohol abuse. The drug disulfiram is prescribed for the patient. This drug deters the consumption of alcohol by which of the following mechanisms? a) Inhibiting the absorption of ethanol so that an individual cannot become intoxicated, regardless of how much he or she drinks b) Inhibiting the conversion of ethanol to acetaldehyde, which cause the excretion of unmetabolized ethanol c) Blocking the conversion of acetaldehyde to acetate which causes the accumulation of acetaldehyde d) Activating the excessive metabolism of ethanol to acetate, which causes inebriation with consumption of a small amount of alcohol e) Preventing the excretion of acetate, which causes nausea and vomiting