Lecture 24: Alcohol Metabolism Flashcards
When present, alcohol becomes the ___ fuel, displacing other fuels
preferred
Alcohol is absorbed ___ and metabolized ___
fast; slowly
Where is ETOH mostly oxidized?
Liver (some in stomach)
What are the two main pathways for ethanol metabolism?
1) ADH pathway of the cytosol (stomach/liver)
2) Microsomal Ethanol Oxidizing System (MEOS) - endoplasmic reticulum of liver
Both pathways result in the production of ___, a highly toxic metabolite
Acetylaldehyde
First pass metabolism of alcohol occurs in the ___
stomach
ADH comprises a family of enzymes that catalyze the conversion of ethanol to ___
acetaldehyde
Even the ____ form of ADH is activated after alcohol ingestion due to high gastric ethanol concentration
high Km
First pass metabolism ___ bioavailability of ethanol
decreases
_____ is a protect barrier against systemic effects of alcohol, which is commonly lost in individuals who suffer from alcohol abuse disorder
First pass metabolism
True or False: For a given amount of alcohol consumed, blood levels are higher in men than women. Why or why not?
False - blood levels are higher in women than men
-Women are smaller, have more fat, and less gastric ADH
How is moderate drinking defined?
Men: Not more than 2 drinks per day
Women: One drink per day
Alcohol + NAD is => acetaldehyde+NADH as a result of what enzyme?
Alcohol Dehydrogenase
What compound overwhelms the liver’s capacity to maintain redox homeostasis?
NADH
Normally, is there greater NAD+ or NADH in the liver? How is this balance shifted?
Typically there is higher NAD+/NADH
-The balance is shifted with alcohol
The inability of the liver to maintain ___ homeostasis is the reason for the metabolic derangement seen when ETOH is consumed
redox
Ethanol is converted to ___ and ___. As a result, what products are made?
acetaldehyde ; acetate
x2 NADH
NADH feeds the ETC, causing the TCA to ___, increased levels of ___ and ___
slow; ATP; acetyl CoA
As a result of ethanol intake (conversion froom acetylaldehyde to acetate) there is elevated acetyl CoA, which can cause synthesis of ____ ____, leading to a disorder known as ____
fatty acids; fatty liver
Ethanol oxidation causes NADH to be made. NADH + pyruvate can make lactate using LDH. Lactic acid build up can lead to?
Hyperlactacidemia
Renal acidosis
Uricacidemia
Gout
When alcohol oxidation occurs, you can convert ___ to ___ but not vice versa. Therefore, you can not undergo gluconeogenesis and, as a result, can develop ______
pryuvate; lactate
-Hypoglycemia
If you are unable to convert lactate to pyruvate, you cannot undergo _____
gluconeogenesis
Lactic acidosis can lead to reduced excretion of ______
Uric Acid
Mitochondria use ____ originating from ethanol rather than those derived from oxidation of fatty acids that normally serve as the main energy source of the liver
hydrogen
An early manifestation of alcohol consumption is the excessive accumulation of fat in the liver, resulting in a condition known as _______
fatty liver
How will increased alcohol consumption affect levels of MEOS (microsomal ethanol oxidizing system)?
Increased MEOS expression and synthesis
____ ____ are the sites for adaptive system of ethanol oxidation named microsomal ethanol oxidizing system
Liver microsomes
MEOS belongs to a class of cytochrome p450 oxidases and oxidation of alcohol involves a specific form of cytochrome P450 oxidase called ____
2E1
____ is highly induced after chronic alcohol consumption
2E1 (CYP2E1)
True or False: 2E1 is highly induced after chronic alcohol consumption whereas hepatic ADH is not inducible
True
The fact that CYP 2E1 is highly induced after chronic alcohol consumption contributes to the metabolic ___ that develops in individuals with alcohol dependence disorders
tolerance
When ethanol is converted to acetylaldehyde, what substrate is used? Product?
NADPH
-NADP+
Which has a higher affinity for alcohol: ADH or P4502E1?
ADH
Under what conditions is P4502E1 most effective?
When large amounts of ETOH are consumed
In what individuals is P4502E1 most effective?
Individuals with ETOH dependence
In social drinkers who also are taking a prescription medication, they will have elevated ETOH blood levels and retain the drug in their system longer. Why?
-Drugs inhibit alcohol oxidation in stomach, leading to elevated alcohol levels
-The alcohol will be down in the liver, but only after the drug does
In alcohol dependent individuals on prescription medications, drugs get broken down in the liver ____, which could lead to less drug in the system and less action of the drug itself. Alcohol also gets broken down in the liver
very fast
In alcohol dependent individuals on prescription medications, alcohol oxidation in the stomach is ___
inhibited
In the non-alcoholic, alcohol is metabolized by __, an enzyme. Drugs, however, are metabolized by the ____ in the lvier
ADH; microsomal cytochrome P450
In the non-alcoholic, how will an increased in alcohol concentration affect drug metabolism in the liver and ADH in the stomach?
In the non-alcoholic, an increase in alcohol concentration will inhibit drug metabolism/ADH in stomach
With chronic drinking, gastric ADH ___ resulting in decreased _______ in the stomach
decreases; ethanol metabolism
In chronic drinkers, liver MEOS is highly ___
induced
True or False: Inducation of MEOS produces other related toxicities. In other words: cytochrome oxidases can convert many exogenous compounds to toxic metabolites
True
Many endogenous and xenobiotic compounds (including: ETOH) are substrates for ___
CYP2E1
Activation of CYP2E1/NADPH can lead to production of _____, activation of ___/____
free radicals; toxins/carcinogens
True or False:
An effect of the induction of the MEOS is the enhanced metabolism of various other drugs (prescribed drugs and OTC meds)? Why is this?
True
-substrate for/inducers of: 2E1
True or False:
On many occasions, metabolites produced in the microsomes are more toxic than the precursor compounds
True
Phase I of Acetaminophen metabolism produces ____, which is highly toxic
NAPQ1
Alcohol reduces glutathioine levels, resulting in increase _____-mediated damage because you make more ___
free radical; NAPQ1
When is NAPQ1 produced in large quantities?
When 2E1 is highly induced
Increase in P4502E1 may partially account for the increase incidence of ___ among persons with ETOH abuse disorder
cancer
Testicular atrophy and gynecomastia are common seen in _____
ETOH abuse
Ethanol is converted to ___ and ___
acetylaldehyde and acetate
Conversion of acetylaldehyde to acetate occurs via what enzyme?
(acetylaldehyde+NAD+ -> acetate + NADH)
ALDL (aldehyde dehydrogenase)
When is the activity of ALDL reduced? What occurs as a result?
Chronic alcohol consumption
-Acetylaldehyde becomes the major end product accumulating in tissues and blood
Acetylaldehyde reacts with cellular constituents like proteins and other macromolecules to cause ____ damage
Free-radical mediated oxidative
Alcohol is energy ___ and individuals with alcohol dependence obtain large proportion of their energy from ethanol, which typically result in decreased intake of non-alcoholic foods containing essential nutrients
dense
The intrinsic toxicity of alcohol can be responsible for some of the nutritional ___ seen in individuals with ETOH abuse
deficiency
What 2 factors contribute to malnutrition in alcohol abuse?
1) maldigestion/malabsorption
2) impaired utilization
What is secondary malnutrition a result of?
Maldigestion and malabsorption
True or False:
Alcohol abuse can alter the GI tract and directly interfere with absorption of certain nutrients
True
Severe liver damage interferes directly with ___, ___, and ___ of certain nutrients
storage, activation, degradation
What causes thiamin deficiency?
Impaired absorption
______ Syndrome is commonly seen in alcoholics due to severe thiamin deficiency
Wenicke-Korsakoff Syndrome
People with ETOH abuse disorder show folic acid/pyridoxine deficiency due to ____ as well as Vitamin A deficiency due to ____
malabsorption; degradation of stored vitamin
Alcoholic Cirrhosis is a result of both ___ and _____
Malnutrition and direct toxic effects of alcohol
Disulfiram (antabuse) causes accumulation of ____, resulting in flushing, tachy, nausea, and hyperventilation. It is commonly used to help individuals stop abusing ETOH.
acetylaldehyde
___ accumulation results in reduced conversion of ___ to ___. This results in impaired gluconeogenesis. Increased lactate causes ____
NADH; lactate; pyruvate; acidosis
Lactic acidosis can lead to a reduction in excretion of _____
Uric acid
In addition to
tolerance to ethanol,
individuals with
alcohol dependence
tend to display
tolerance to various
other ___
Drugs
