Alcohol Metabolism

Question 1

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

Answer 1

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

Question 2

what does liver damage do?

Answer 2

it lowers alcohol oxidation and elimination rates from the body

Question 3

is alcohol stored?

Answer 3

nope - it stays in body water until eliminated

Question 4

where are carbohydrates stored?

Answer 4

glycogen is stored in liver and muscle

Question 5

where is fat stored?

Answer 5

TAGs are stored in the adipose tissue and liver

Question 6

is there hormonal regulation not pace rates of alcohol elimination?

Answer 6

not really, very little

Question 7

does alcohol elimination follow Michaelis-Menden kinetics?

Answer 7

yes

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

Question 8

what are the general 3 steps that drive ethanol oxidation?

Answer 8

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)

Question 9

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

Answer 9

cytochrome p450E1

influences alcohol metabolism and can subsequently influence alcohol drug interactions

Question 10

what do cytochrome p450s do?

Answer 10

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

Question 11

what does cytochrome P450 do?

Answer 11

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

Question 12

what does CYP2E1 do?

Answer 12

• 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

Question 13

what are the 4 enzymes that contribute to alcohol oxidation?

Answer 13

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

Question 14

where is ADH located? what does it do?

Answer 14

cytosol

inside the cell

converts alcohol to acetaldehyde

Question 15

where is catalase found? what does it do?

Answer 15

peroxisome

requires H2O2 to oxidize alcohol

Question 16

where is CYP2E1 found? what does it do?

Answer 16

predominantly in the cell’s microsomes

metabolizes ethanol to acetaldehyde at elevated ethanol concentrations

Question 17

where is ALDH found? what does it do?

Answer 17

in the mitochondria

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

Question 18

what role does mitochondria play in alcohol metabolism?

Answer 18

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

Question 19

what is the big reason alcohol metabolism toxic to cells?

Answer 19

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

Question 20

which enzyme does acetaldehyde inhibit?

Answer 20

it’s a product inhibitor of ADH

Question 21

what are some reasons alcohol metabolism is toxic to cells?

Answer 21

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

Question 22

how does acetaldehyde impact mitochondrial function?

Answer 22

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

2. 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

Question 23

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

Answer 23

alcohol causes a high NADH/NAD+ ratio

aka a low NAD+/NADH ratio

alcohol metabolism increases NADH levels

Question 24

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

Answer 24

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

Question 25

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

Answer 25

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

Question 26

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

Answer 26

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

Question 27

what happens when there's high NADH levels?

Answer 27

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

Question 28

when does alcoholic ketoacidosis happen?

Answer 28

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

Question 29

why does alcohol metabolism stimulate lipolysis?

Answer 29

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

Question 30

what increases ketone production?

Answer 30

being malnourished or vomiting patients or if you're hypophosphatemic

Question 31

what's alcoholic ketoacidosis?

Answer 31

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

Question 32

what is diabetic ketoacidosis?

Answer 32

``` acidosis ketosis hyperglycemia high ketones high glucose ```

Question 33

what's the difference between AKA and DKA?

Answer 33

DKA have very high glucose levels while AKA has normal/low glucose levels both have acidosis, ketosis, and high ketones

Question 34

what medication is used to treat alcoholism?

Answer 34

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

Question 35

which nutrient is deficient in alcoholics?

Answer 35

thiamine

Question 36

what does thiamine deficiency from chronic alcoholism cause?

Answer 36

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

Question 37

what does thiamine deficiency do to the heart?

Answer 37

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

Question 38

what does thiamine deficiency do to the nervous system?

Answer 38

alcohol linked-neurological disorder called Wernicke-Korsakoff syndrome also alcoholic dementia and cerebellar atrophy

Question 39

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

Answer 39

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

Question 40

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

Answer 40

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

Question 41

which enzymes require thiamine as a cofactor for their activity?

Answer 41

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

Question 42

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

Answer 42

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

Question 43

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?

Answer 43

thiamine supplementation

Question 44

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 :

Answer 44

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