Alcohol Metabolism

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Metabolism of alcohol in the liver produces

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acetate

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Ethanol metabolism occurs in

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fed state liver

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Starters for ethanol metabolism

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ethanol and NAD+

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products of ethanol metabolism

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acetate and NADH

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toxic intermediate of ethanol metabolism

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acetladheyde

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what happens in ethanol metabolism

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oxidation of ethanol carbons and reduction of NAD+

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Ethanol metabolism enzymes

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ADH or MEOS convert ethanol to acetyladehyde

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moderate ethanol consumption uses

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ADH

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higher amounts of ethanol consumption use

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MEOS via P450 enzyme CYP2E1

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ALDH convert

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acetyladehyde to acetate

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MEOS happens on

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ER

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NADPH processed w

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MEOS

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Molecular O2 is

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used as the ultimate oxidizing agent by this and other cytochrome P450 enzymes. This O2 is reduced to H2O.

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Ehtanol inhibits

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other P450 systems

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hepatic can use this acetate (acetyl coA) for

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TCA, FA synthesis--> TAG synthesis, ketones, cholesterol

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acetate from ethanol is converted to

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acetyl coA w ATP needed to make high energy CoA bond

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Depends on fed/fast but acetyl coA becomes

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OAA then citrate then TCA cycle or FA synthesis, chol synth, ketone synth

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NADH from ethanol metabolism can be re-oxidized by

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ox-phos or redehydrogenase reactions

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Too high NADH will

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cause hepatic dehydrogenase reactions to occur in the reverse direction from that needed.
Negatively impact hepatic metabolism

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acetate unused by liver goes to

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extrahepatic tissues skeleta lmuscle, heart, and kindey

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Alcohol dehydrogenase and acetaldehyde dehydrogenase are not regulated

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by NADH/NAD+ or ATP/ADP-AMP levels.

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Abnormally high NADH decreases

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TCA cycles, beta oxidation, glycolysis

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abnormally high NADH increases

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G3P synthesis, pyruvate--> lactate, OAA --> malate

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Beta oxidation and G3PDH both need

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NAD+ this is reduced w high levels of ethanol bc all goes to NADH

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Fatty liver develops w high ethanol bc

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incr TAG synthesis bc incr substrate from G3P synthesis of DHAP and decr b-oxid = high FA levels

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Liver damage bc high acetyladehyde bc

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decr protein synthesis so decr lipoprotein synthesis, decr liporprotein export

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Ketoacidosis is secondary occurs bc

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abn NADH decr TCA, acetyl coA to TCA is also decr.. so acetyl coA levels increase..which incr ketone synthesis to use up acetyl coA

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Decreased catabolism of ketone bodies BC

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skeletal, kidney, and heart rather prefer breakdown of acetate

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lactic acidosis is also secondary

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high NADH will incr pyruvate--> lactate, liver wont use it as much so it builds up in bloodstream

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Gouter also secondary

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uric deposits in joints bc lactate competes with uric acid for excretion by the kidney.

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Hypoglycemia secondary occurs in fast bc

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decreased hepatic lactate uptake occurs, Considerable pyruvate from transamination of alanine is converted to lactate instead of to glucose.
Alanine carbons go to lactate instead of gluconeogenesis, G3P not converting to DHAP..less glucogenic substrates

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Hyperglycemia in fed is secondary

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high NADH decr hepatic glycolysis

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high ethanol = high acetyladehyde bc

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ALDH2 genotype may still be low so builds up acetylaldehyde

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Acetaldehyde binds to

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amino acids

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Protein synthesis is decreased as a result of acetyladeyde binding to AA bc

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lack of necessary apoproteins.

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Acetaldehyde binds to glutathione

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decreasing its antioxidant activity.

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decrease in antioxidant will

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increase free radical formations, Increased CYP2Y1 activity in the MEOS system also increases free radical formation.
Increased CYP2Y1 (and other P450 enzyme) induction can also increase free radical generation either directly or by increasing drug and toxin metabolism.

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ROS affect

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Phospholipids and hence membranes are especially affected.
The liver’s ability to remove proteins - including the lipoprotein VLDL - decreases as a result.
VLDL buildup contributes to development of a fatty liver.

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Ethanol-induced hepatitis due to inflamed

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and ultimately nonviable liver cells may result.

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To correct for hepatic damage, the liver attempts

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wound healing

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Connective tissue (especially collagen) synthesis is increased.

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fibrosis results

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fibrosis and a fatty liver result in irreversible hepatic damage.

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cirrhosis occurs

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metabolism of ethanol

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varies from individual to individual

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increased ethanol

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results in induction of the genes for both ADH and ALDH.

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several alcohol dehydrogenase (ADH) isoenzymes.

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ADH1 and ADH2 in liver

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ADH 1 occurs in

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in three possible genotypes with different levels of activity.

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ADH 2 is active only

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with higher levels of ethanol ingestion

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ADH 4 occurs

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in the GI tract and catabolizes mainly excess ethanol relative to ADH 1 and 2 capacity.

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The cytosolic form of ALDH

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oxidizes minor amounts of acetaldehyde.

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One common genetic variant of the mitochondrial ALDH has relativel

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low activity, resulting in toxic levels od acetyladhehyde

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Decreased acetaldehyde clearance due to this mitochondrial ALDH phenotype leads to

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nausea, vomiting, and - especially in homozygotes - avoidance of ethanol.

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genes for CYP2E1 are induced at

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several levels of protein synthesis in response to increased ethanol levels

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Degradation of CYP2E1 is inhibited

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high ethanol levels

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CYP2E1 and the other P450 enzymes are essentially

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isoenzymes in that they have overlapping specificities for both the compounds they metabolize and for compounds inducing their synthesis

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Different genotypic forms of CYP2E1

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lead to different responses to ethanol ingestion in different individuals.