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Alcohol Metabolism

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Alcohol

  • Alcohol we consume = ethanol, ethyl alcohol, EtOH (all interchangeable)

    • CH3-CH2-OH​

  • purely exogenous

  • 4th energy source (after carbs, protein, fat)

    • 7 kcal/g of empty calories, does not provide energy​

​

  • Absorbed through the whole GI tract

  • dissolves well and transported unaltered in blood

  • toxicity is 50-100 mg/dL

  • high lipid solubility 

    • can pass membranes easily

  • oxidative degradation in tissues

METABOLISM

  • EtOH cannot be stored so it's metabolism takes priority

  • Three pathways:

  1.  alcohol dehydrogenase (ADH) pathway in cytosol​

  2.  microsomal ethanol oxidizing system (MEOS) in the ER

  3. catalase in the peroxisomes

  • all three pathways produce acetaldehyde

    • highly toxic​

    • converted to acetate

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  • 1. ADH PATHWAY

    • main system​

    • mainly in liver

    • some in stomach (gastric mucosa)

    • men>women

      • females develop higher blood alcohol levels than their male counterparts at equal consumption​

  • 2. MEOS PATHWAY

    • second system

    • used when more EtOH gets into cells than the ADH system can tolerate

    • inducible

  • 3. Catalase-H2O2 system

    • minor role​

    • only accounts for <2% EtOH

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ADH with NAD depletion

Oxidation (via dehydrogenation)

  • NAD + 2H                      NADH + H 

  • fixed amount - one form of the other

  • only ratio of NADH/NAD+ changes

  • increased ADH activity (priority) limits availability of NAD+ for other dehydrogenations

  • increased NADH/NAD ratio

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Consequences of low NAD/NADH: 

  • slows reactions that require NAD and e- and H+ acceptor

  • slows lactate --> pyruvate, leads to lactic acidosis

    • slows TCA cycle because NAD is needed for

      • isocitrate --> α-KG​

      • α-KG --> succinyl CoA

      • malate --> OAA

      • results in increased citrate, therefore increase FA synthesis

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Low NAD/NADH

  • DHAP has two choices

    • G3P to continue to glycolysis

    • G3P acts as a precursor to TAG synthesis

  • ratio favors G3P formation

    • FA synthesis is already elevated to begin with​

    • backbone and FA components for TAG synthesis --> beer belly

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MEOS

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  • detoxification system

  • contains cytochrome P450

    • intermediate e- carrier​

  • this system becomes important when ADH is saturated

  • oxidizes a wide variety of compounds in addition to EtOH

    • FAs​

    • aromatic hydrocarbons

    • steroids

  • bypasses first dehydrogenation step of ADH

    • less NADH is produced for ETS​

  • instead linked to the oxidation of NADPH by O2

  • therefore, 2 substrates are oxidized at once

    • NADPH and EtOH​

      • each gets oxidized by one of the O from O2​

      • 2 H2O formed in process

      • that's why it's called "mixed function" oxidases

  • MEOS enzymes are inducible and don't just metabolize EtOH

  • when induced, can metabolize/process EtOH more efficiently

    • --> metabolic tolerance​

    • can ingest larger quantities

    • can speed up the metabolism of other compounds

Consequences

Overconsumption (alcoholism):

  • fatty liver disease

  • hepatic disease (cirrhosis)

  • lactic acidosis

  • metabolic tolerance

Explained by: 

  • increased NAD/NADH ratio

  • acetaldehyde toxicity 

    • produced from both detox systems​

    • can covalently attach to proteins and cause impairment

    • may be associated with cirrhosis

  • metabolic competition

  • induced metabolic tolerance

​

EtOH is like dr. jekyll and mr. hyde

  • the role depends on how much is consumed

  • bad effects include

    • hypertension​

    • increased bone loss in men

    • nutrient malabsorption

    • fetal alcohol syndrome

    • brain damage

    • alcohol amnesic disorder

    • CANCER

effects of intoxication

  • sympathetic and adrenomedullary responses

  • mobilization of fatty acids from peripheral adipose tissue

  • hypoxia and disturbances in blood flow through various organs may account for much of the variability in metabolism of ethanol itself, as well as its effects on metabolism of other systems

hard to predict effects of ethanol consumption in individuals

  • gender differences

  • different effects at different levels of intake

  • variation in associated nutritional imbalances

  • variations in hepatic pathology which may occur with chronic consumption

vitamin deficiencies

  • liver is a major storage site for certain vitamins, as well as activating some

  • most common: FOLIC ACID

    • increased demands for nucleic acids to regenerate liver cells that are damaged​

  • thiamin (B1), nicotinic acid (B3), vitamin K (involved in blood clotting) , vitamin B12

substrate competition

  • especially with vitamin A (retinol --> retinal)

  • EtOH competes for enzymes that metabolize and activate vitamin A

  • also may interfere with vitamin A inducing the MEOS

Other effects: 

  • may exhibit a J-shaped curve for relationship to obesity 

Beneficial effects!​

  • many studies suggest that alcohol in moderation may: 

    • decrease CVD risk, increase HDL and decrease Lp(a)​

    • may improve insulin sensitivity

    • studies showing benefits may be flawed

direct pharmacological action of ethanol

  • ethanol may reduce active transport of amino acids in the liver, GI tract and elsewhere

  • it may also have a direct effect on: 

    • synthesis and exocytosis of lipoproteins in the liver​

    • renal tubular transport mechanisms

    • permeability of mitochondrial and cell membranes

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©2023 by Syracuse University Dr.Margaret Voss

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