Alcohol Metabolism Flashcards
where are the major enzymes involved with ethanol oxidation usually present?
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
what does liver damage do?
it lowers alcohol oxidation and elimination rates from the body
is alcohol stored?
nope - it stays in body water until eliminated
where are carbohydrates stored?
glycogen is stored in liver and muscle
where is fat stored?
TAGs are stored in the adipose tissue and liver
is there hormonal regulation not pace rates of alcohol elimination?
not really, very little
does alcohol elimination follow Michaelis-Menden kinetics?
yes
the rate of change in alcohol concentration depends on the concentration of alcohol and kinetic constants Km and Vmax
what are the general 3 steps that drive ethanol oxidation?
this 3-step process gets rid of ethanol in the body
- 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
- aldehyde dehydrogenase (ALDH) oxidizes acetaldehyde to acetate - NAD+ cofactor is reduced to NADH - essentially irreversible - acetaldehyde levels are lower under normal conditions
- 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)
what other enzyme plays a role in alcohol oxidation other than ADH and ALDH?
cytochrome p450E1
influences alcohol metabolism and can subsequently influence alcohol drug interactions
what do cytochrome p450s do?
they’re a family of heme enzymes that are involved in the oxidation of steroids, FA and xenobiotics ingested from the environment
what does cytochrome P450 do?
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
what does CYP2E1 do?
- 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
what are the 4 enzymes that contribute to alcohol oxidation?
- ADH
- ALDH
- cytochrome P450 2E1 (CYP2E1)
- catalase
where is ADH located? what does it do?
cytosol
inside the cell
converts alcohol to acetaldehyde
where is catalase found? what does it do?
peroxisome
requires H2O2 to oxidize alcohol
where is CYP2E1 found? what does it do?
predominantly in the cell’s microsomes
metabolizes ethanol to acetaldehyde at elevated ethanol concentrations
where is ALDH found? what does it do?
in the mitochondria
acetaldehyde is metabolized mainly by aldehyde dehydrogenase 2 in the mitochondria to form acetate and ROS
what role does mitochondria play in alcohol metabolism?
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
what is the big reason alcohol metabolism toxic to cells?
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
which enzyme does acetaldehyde inhibit?
it’s a product inhibitor of ADH
what are some reasons alcohol metabolism is toxic to cells?
- redox sate changes in the NADH/NADH ratio
- acetaldehyde formation
- mitochondrial damage
- cytokine formation (TNF)
- Kupffer cell activation
- membrane actions of ethanol
- hypoxia
- immune actions
- oxidative stress
how does acetaldehyde impact mitochondrial function?
- 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
- 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
what does alcohol metabolism do to the NAD+/NADH ratio?
alcohol causes a high NADH/NAD+ ratio
aka a low NAD+/NADH ratio
alcohol metabolism increases NADH levels
how does the NAD/NADH ratio impact metabolism? what happens to the major gluconeogensis precursors?
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
- 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
- also oxaloacetate is shunted to malate to also help regenerate NAD+ for alcohol metabolism
- 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
is glycogen effected by the low NAD/NADH ratio produced from alcohol metabolism?
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
which reactions are inhibited because of the decreased NAD+/NADH ratio?
- glycolysis
- citric acid cycle (ketogenesis favored)
- pyruvate dehydrogenase
- FA oxidation
- glucogeneogensis
all of these produce NADH so they’re inhibited by the high amounts of NADH being produced from alcohol metabolism
what happens when there’s high NADH levels?
- pyruvate –> lactate
- metabolic acidosis and increased respiration rate
- hypoglycemia from low pyruvate - increase ketone bodies from acetyl CoA (ketosis)
- 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
when does alcoholic ketoacidosis happen?
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
why does alcohol metabolism stimulate lipolysis?
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
what increases ketone production?
being malnourished or vomiting patients or if you’re hypophosphatemic
what’s alcoholic ketoacidosis?
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
what is diabetic ketoacidosis?
acidosis ketosis hyperglycemia high ketones high glucose
what’s the difference between AKA and DKA?
DKA have very high glucose levels while AKA has normal/low glucose levels
both have acidosis, ketosis, and high ketones
what medication is used to treat alcoholism?
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
which nutrient is deficient in alcoholics?
thiamine
what does thiamine deficiency from chronic alcoholism cause?
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
what does thiamine deficiency do to the heart?
increases blood flow through the blood vessels which leads to heart failure and sodium and water retention in the blood
what does thiamine deficiency do to the nervous system?
alcohol linked-neurological disorder called Wernicke-Korsakoff syndrome
also alcoholic dementia and cerebellar atrophy
how can alcohol metabolism lead to both lipolysis and FA synthesis?
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
how does thiamine deficiency lead to alcohol-related brain damage?
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
which enzymes require thiamine as a cofactor for their activity?
- transketolase (pentose phosphate pathway)
- pyruvate dehydrogenase (glycolysis, makes acetyl CoA)
- alpha ketogluterate dehydrogenase (TCA cycle, makes succinyl-CoA
thiamine deficiency leads to big reduction in the activity of these enzymes and brain cells
what are the different things that can lead to thiamine deficiency?
- inadequate dietary intake
- malabsorption from the GI tract
- impaired utilization of thiamine in cells
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?
thiamine supplementation
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 :
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
