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TBL 1 > Alcohol Metabolism > Flashcards

Alcohol Metabolism Flashcards

1
Q

where are the major enzymes involved with ethanol oxidation usually present?

A

major enzyme systems responsible for ethanol oxidation, alcohol dehydrogenase and to a lesser extent, the cytochrome P450-dependent ethanol oxidizing system are present to the largest extent in the liver

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2
Q

what does liver damage do?

A

it lowers alcohol oxidation and elimination rates from the body

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3
Q

is alcohol stored?

A

nope - it stays in body water until eliminated

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4
Q

where are carbohydrates stored?

A

glycogen is stored in liver and muscle

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5
Q

where is fat stored?

A

TAGs are stored in the adipose tissue and liver

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6
Q

is there hormonal regulation not pace rates of alcohol elimination?

A

not really, very little

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7
Q

does alcohol elimination follow Michaelis-Menden kinetics?

A

yes

the rate of change in alcohol concentration depends on the concentration of alcohol and kinetic constants Km and Vmax

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8
Q

what are the general 3 steps that drive ethanol oxidation?

A

this 3-step process gets rid of ethanol in the body

  1. alcohol dehydrogenase (ADH) in the liver is used to oxidize ethanol and make acetaldehyde - NAD+ is reduced to NADH and H+ so two hydrogens are removed from alcohol - this reaction is reversible
  2. aldehyde dehydrogenase (ALDH) oxidizes acetaldehyde to acetate - NAD+ cofactor is reduced to NADH - essentially irreversible - acetaldehyde levels are lower under normal conditions
  3. most of the acetate produced leaves the liver and goes to peripheral tissues where it’s activated to acetyl CoA - acetyl CoA is also produced from carbohydrates, far and excess protein oxidation - so alcohol ends up as the same products formed from oxidation of carbs, fats and protein such as CO2, FA, ketone bodies, and cholesterol (depends on energy state and nutritional conditions of the body)
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9
Q

what other enzyme plays a role in alcohol oxidation other than ADH and ALDH?

A

cytochrome p450E1

influences alcohol metabolism and can subsequently influence alcohol drug interactions

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10
Q

what do cytochrome p450s do?

A

they’re a family of heme enzymes that are involved in the oxidation of steroids, FA and xenobiotics ingested from the environment

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11
Q

what does cytochrome P450 do?

A

it modifies alcohol-drug interactions

since ethanol and certain drugs compete for metabolism by CYP2E1, a p450 enzyme, active drinkers will often display an enhanced sensitivity to certain drugs because alcohol inhibits the metabolism of the drug which prolongs its half-life

since CYP2E1 is induced after chronic alcohol consumption, metabolism of drugs that are also substrates for CYP2E1 will be increased

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12
Q

what does CYP2E1 do?

A
  • it’s a minor pathway for alcohol metabolism
  • produces acetaldehyde, 1-hydroxyethyl radical
  • responsible for alcohol-drug interactions
  • activates toxins such as acetaminophen, CC14, halothane, benzene, halogenated hydrocarbons to reactive toxic intermediates
  • activates pro carcinogens such as nitrosamines, ado compounds to active carcinogens
  • acitivates molecular oxygen to reactive oxygen species such as superoxide radical anion, H2O2 hydroxyl radical
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13
Q

what are the 4 enzymes that contribute to alcohol oxidation?

A
  1. ADH
  2. ALDH
  3. cytochrome P450 2E1 (CYP2E1)
  4. catalase
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14
Q

where is ADH located? what does it do?

A

cytosol

inside the cell

converts alcohol to acetaldehyde

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15
Q

where is catalase found? what does it do?

A

peroxisome

requires H2O2 to oxidize alcohol

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16
Q

where is CYP2E1 found? what does it do?

A

predominantly in the cell’s microsomes

metabolizes ethanol to acetaldehyde at elevated ethanol concentrations

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17
Q

where is ALDH found? what does it do?

A

in the mitochondria

acetaldehyde is metabolized mainly by aldehyde dehydrogenase 2 in the mitochondria to form acetate and ROS

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18
Q

what role does mitochondria play in alcohol metabolism?

A

it plays a role in alcohol metabolism via ALDH which is located in the mitochondria

ALDH catalyzes the conversion of acetaldehyde to acetate

when ALDH reaches a saturation point, the acetaldehyde escapes into the blood stream and leads to damage to biomolecules like lipids, proteins and nucleic acids which results in the toxic side effects associated with alcohol consumption

19
Q

what is the big reason alcohol metabolism toxic to cells?

A

formation of acetaldehyde

it’s a reactive compound that can interact with thiol and amino groups of AA in proteins which can cause inhibition of that protein’s function and/or cause an immune response

so ALDH is very important because it removes acetaldehyde and other aldehydes

effective removal of acetaldehyde is important to prevent cellular toxicity and maintain efficiency removal of alcohol

20
Q

which enzyme does acetaldehyde inhibit?

A

it’s a product inhibitor of ADH

21
Q

what are some reasons alcohol metabolism is toxic to cells?

A
  1. redox sate changes in the NADH/NADH ratio
  2. acetaldehyde formation
  3. mitochondrial damage
  4. cytokine formation (TNF)
  5. Kupffer cell activation
  6. membrane actions of ethanol
  7. hypoxia
  8. immune actions
  9. oxidative stress
22
Q

how does acetaldehyde impact mitochondrial function?

A
  1. mitochondrial ALDH2 converts acetaldehyde to acetate

when ALDH2 is malfunctioning or oversaturated then acetaldehyde increases damages to the electron transport complex I-IV which leads to production of ROS which affects the ETC and oxidative phosphorylation which disrupts ATP synthesis

  1. oxidative stress affects permeability of outer/inner mitochondrial membranes

promotes opening of the permeability transition pore(PTP) which favors the translocation of the pro-apoptotic factor bax which forms a complex with voltage-dependent anion channel (VDAV) - when mitochondrial permeability transition is extensive it causes mitochondrial swelling and permits the cytochrome c release, caspase action and DNA fragmentation = apoptosis

23
Q

what does alcohol metabolism do to the NAD+/NADH ratio?

A

alcohol causes a high NADH/NAD+ ratio

aka a low NAD+/NADH ratio

alcohol metabolism increases NADH levels

24
Q

how does the NAD/NADH ratio impact metabolism? what happens to the major gluconeogensis precursors?

A

lots of NADH is produced during alcohol oxidation

since liver glycogen stores have been depleted within 36 hours of fasting, gluconeogenesis is required to maintain blood glucose levels

the major precursors to gluconeogenesis are glycerol, lactate and AA which gives rise to pyruvate or TCA cycle precursors which generate oxaloacetate

  1. because of the low NAD+/NADH ratio from alcohol metabolism, pyruvate destined for gluconeogeneis is shunted to lactate to regenerate NAD+ and allow alcohol metabolism to continue
  2. also oxaloacetate is shunted to malate to also help regenerate NAD+ for alcohol metabolism
  3. glycerol that’s converted to glycerol-3-phosphate can’t go to dihydroxyacetone phosphate due to high NADH levels in the liver

so low NAD+/NADH ratio diverts gluconeogenic precursors from entering gluconeogenesis and causes the liver to have problems maintaining adequate blood glucose levels

25
Q

is glycogen effected by the low NAD/NADH ratio produced from alcohol metabolism?

A

no

glycogen stores are depleted after 36 hours of fasting but glycogen regulation isn’t affected by the NAD/NADH ration

when the liver is exporting glucose like during glucagon administration, liver glycolysis is inhibited by covalent modification of regulatory enzymes, not the NAD/NADH ratio

26
Q

which reactions are inhibited because of the decreased NAD+/NADH ratio?

A
  1. glycolysis
  2. citric acid cycle (ketogenesis favored)
  3. pyruvate dehydrogenase
  4. FA oxidation
  5. glucogeneogensis

all of these produce NADH so they’re inhibited by the high amounts of NADH being produced from alcohol metabolism

27
Q

what happens when there’s high NADH levels?

A
  1. pyruvate –> lactate
    - metabolic acidosis and increased respiration rate
    - hypoglycemia from low pyruvate
  2. increase ketone bodies from acetyl CoA (ketosis)
  3. FA synthesis and TAG formation which accumulates in the liver (FA synthesis does NADPH –> NADP+) = fatty liver syndrome

the liver reacts to increase in FA synthesis by increasing protein synthesis and exporting liposomes as lipoproteins = increased blood lipid levels = hyperlipidemia

28
Q

when does alcoholic ketoacidosis happen?

A

alcoholic ketoacidosis occurs when NAD+ is depleted by ethanol metabolism which results in inhibition of the aerobic metabolism in the TCA cycle, depletion of glycogen stores, ketone formation and lipolysis stimulation

29
Q

why does alcohol metabolism stimulate lipolysis?

A

alcohol metabolism depletes glycogen stores and surpassed insulin secretion; glucagon and catecholamines are stimulated

this environment stimulates lipolysis:

acetyl CoA from lipolysis is metabolized into B-hydroxybutyrate and acetoacetate (ketoacids):

AcAc + NADH –> BHB + NAD

since NAD+ levels are low, BHB is the predominate ketone formed

30
Q

what increases ketone production?

A

being malnourished or vomiting patients or if you’re hypophosphatemic

31
Q

what’s alcoholic ketoacidosis?

A

AKA is attributed to the combined effects of consumption of large amounts of ethanol and malnutrition

less food intake means less available glucose which leads to depletion of glycogen stores which leads to increased lipolysis and ketogenesis

ethanol inhibits glucose production = hypoglycemia after glycogen stores are depleted

common AKA characteristic = increased ketone body concentration

LOW blood glucose

32
Q

what is diabetic ketoacidosis?

A 
acidosis
ketosis
hyperglycemia
high ketones
high glucose
33
Q

what’s the difference between AKA and DKA?

A

DKA have very high glucose levels while AKA has normal/low glucose levels

both have acidosis, ketosis, and high ketones

34
Q

what medication is used to treat alcoholism?

A

antabuse which is disulfiram

this blocks the activity of aldehyde dehydrogenase

leads to a severe hangover and can act as a deterrent to promote behavioral modifications in alcoholics

35
Q

which nutrient is deficient in alcoholics?

A

thiamine

36
Q

what does thiamine deficiency from chronic alcoholism cause?

A

alcohol-induced brain damage & heart failure

thiamine comes from our food and function in carbohydrate catabolism, neurotransmitter production and FA production

cells of the nervous system and heart are most sensitive to thiamine deficiency

37
Q

what does thiamine deficiency do to the heart?

A

increases blood flow through the blood vessels which leads to heart failure and sodium and water retention in the blood

38
Q

what does thiamine deficiency do to the nervous system?

A

alcohol linked-neurological disorder called Wernicke-Korsakoff syndrome

also alcoholic dementia and cerebellar atrophy

39
Q

how can alcohol metabolism lead to both lipolysis and FA synthesis?

A

it depends on the amount of alcohol consumed in a certain time period - whether or not it is enough to deplete NAD+

Alcohol is converted to acetyl CoA which is a substrate for fatty acid synthesis, but to become acetyl co A, the enzymes ADH and ALDH use NAD+ to form NADH

If too much alcohol is consumed at once, NAD+ will be depleted, and then aerobic metabolism will not be able to continue, thus forcing the body to switch to anaerobic metabolism to make more NAD+ from pyruvate which will consume all the glycogen stores and force the body to switch to lipolysis for the energy

40
Q

how does thiamine deficiency lead to alcohol-related brain damage?

A

thiamine is an important cofactor for lots of enzymes involved in brain cell metabolism that are required for the production of precursors for several important cell components as well as for energy generation

41
Q

which enzymes require thiamine as a cofactor for their activity?

A
  1. transketolase (pentose phosphate pathway)
  2. pyruvate dehydrogenase (glycolysis, makes acetyl CoA)
  3. alpha ketogluterate dehydrogenase (TCA cycle, makes succinyl-CoA

thiamine deficiency leads to big reduction in the activity of these enzymes and brain cells

42
Q

what are the different things that can lead to thiamine deficiency?

A
  1. inadequate dietary intake
  2. malabsorption from the GI tract
  3. impaired utilization of thiamine in cells
43
Q

A 57 yo man is brought to the ER by a family member that found him very confused, disoriented, and with an unsteady gait and irregular eye movements. The patient has been a heavy drinker for 10 yrs. Examination showed normal pulse and blood pressure. Urine drug screen was negative, yet blood alcohol was very high. Blood pyruvate and lactate levels were normal. Which of the following treatments might help in relieving the symptoms of this patient?

A

thiamine supplementation

44
Q

A 39 yo woman is brought to the emergency room complaining of weakness and dizziness. She recalls getting up early that morning to do her weekly errands and had skipped breakfast. She drank a cup of coffee for lunch and had nothing to eat during the day. She met with friends at 8pm and had several drinks. As the evening progressed, she soon became weak and dizzy and was taken to the hospital. Lab test revealed her blood glucose to be 45mg/dl (normal = 70-99). She was given orange juice and immediately felt better. The biochemical basis of her alcohol-induced hypoglycemia is an increase in :

A

NADH/NAD ratio

The oxidation of ethanol to acetate by dehydrogenase is accompanied by the reduction of NAD+ to NADH. The rise in the NADH/NAD ratio shifts pyruvate to lactate and oxaloacetate to malate, decreasing the availability of substrates for the gluconeogenesis and resulting in hypoglycemia.

The rise in NADH also reduces the NAD+ needed for FA oxidation. The decrease in the oxaloacetate shunts and acetyl coA produced to ketogenesis

Note that the inhibition of FA oxidation results in the re-esterification of the triacylglycerol that can result in fatty liver

TBL 1 (5 decks)

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