Ethanol Metabolism Flashcards
What is the 4th major nutrient that provides a significant amount of energy in many people?
Ethanol
How many kcal/g in alcohol?
7
Calories of alcohol
A lot of calories, although they are empty calories because they have no nutritional value
How many grams of alcohol does the “standard drink” have?
14 grams
What is the estimated calories in a drink (minus the mixers used)
98
What is the 3rd leading preventable cause of death?
Alcoholism
What percentage of men meet the criteria for alcoholism?
17%
What percentage of women meet the criteria for alcoholism?
8%
Affects of over drinking on brain?
Interferes with the brain’s communication pathways
Affect of drinking on heart
Can damage the heart leading to cardiomyopathy, arrhythmias, stoke, high blood pressure
Drinking affects on liver
Steatosis, alcoholic hepatitis, fibrosis, cirrhosis
What is the 1st severely damaged organ from drinking?
Liver
Affects of drinking on pancreas
Produces toxic substances that can lead to pancreatitis
Affects of drinking on eyes
Short and long term vision problems
What is over consumption of alcohol a risk factor for?
Many cancers
What does over consumption of alcohol interfere with?
Proper function of the immune system therefore decrease the body’s ability to fight infections
Solubility of ethanol
Both water and fat soluble
Absorption of alcohol into the intestine
Very easily absorbed by the intestine and readily enters the blood stream because of the fat and water soluble characteristics of ethanol
Where can a small amount of ethanol be metabolized?
By cells in the upper GI tract
What happen to a small amount of ethanol?
Lost through the lungs and kidneys
Where is the majority of ethanol processed?
In the liver via 2 pathways
What are the two pathways that liver can process ethanol?
- Involves alcohol dehydrogenase (ADH)
2. Uses the microsomal ethanol oxidizing systems (MEOS) relying on cytochrome P450 enzymes
What do we even have enzymes to process alcohol?
Intestinal bacteria will produce ethanol via fermentation, that’s why we have the enzyme to break it down
Where does ethanol metabolism predominantly happen?
Liver
Ethanol metabolism via MEOS
10-20%
Extremely upregulated
Ethanol metabolism via ADH system
- 80-90%
- uses ADH and ALDH
What is the damaging molecule of excessive drinking?
Acetaldehyde H3C-CHO
What does ADH do to ethanol?
Converts it to acetaldehyde
What is the rate limiting step in ethanol metabolism?
ADH and the availability of NAD+
What is another limiting factor for alcohol metabolism other than ADH?
Availability of NAD+
What is the Km of ADH for ethanol?
Near 1 mmol/L
When does the enzyme get saturated when drinking alcohol?
ADH gets saturated essentially after one drink, and alcohol metabolism follows zero order kinetics
What kind of kinetics does alcohol metabolism follow?
Zero order kinetics
What happens when ADH is saturated?
Additional ethanol circulates in blood until active site opens up
How much alcohol does a person metabolize per hour?
About 10g of alcohol per hour
How does the blood alcohol level decrease per hour?
By about 0.15g/L every hour. Important calculations after car accidents
ALDH in east asians
Atypical with a single amino acid substitution
Glu—Lys
Dominant negative mutation of ALDH
- Single amino acid mutation of ALDH of glu—lys
- -even heterozygotes, who still produce the normal enzyme in addition to the defective one, have near zero enzyme activity
What happens to someone with atypical ALDH when they drink?
The toxic acetaldehyde accumulates to high levels after only one or two drinks
Oriental flush response
- asians typically have atypical ALDH
- causes vasodilation, facial flushing, tachycardia
Rate of alcoholism in asians
Barely any. Oriental flush response is so unpleasant that no one wants to drink
What percentage of asians have atypical ADH?
30-40%
What is one symptom of acetaldehyde toxicity?
Flushing of the face and nausea
This inhibits aldehyde dehydrogenase, which will result in the accumulation of acetaldehyde after ingestion of alcohol.
Disulfiram
What is disulfiram used for?
As a deterrent from drinking from the sickness that will result
What happens if a person is on disulfiram and still drinks?
The damage caused by acetaldehyde that is seen in long time alcoholics will be accelerated
What is another compound that will have a more immediate affect on ethanol metabolism?
NADH
What does the processing of alcohol in the liver produce?
Large quantities of NADH in the liver
Drinking only a moderate amount of alcohol and NADH in liver
Likely that it will not result in significant changes (unless fasting)
Large amount of NADH building up
Alter many metabolic processes
When are significant effects of NADH build up seen?
Found mainly in heavy drinkers, or occasional drinkers that binge
Large build up of NADH in well fed state
When the liver is taking up glucose and performing glycolysis producing NADH and pyruvate, high levels of NADH will inhibit PDH complex and cause pyruvate to be converted into lactate resulting in lactic acidosis
Secondary effect of lactic acidosis
Will be the underexcretion of uric acid, resulting in hyperurecima
Build up of large amounts of NADH in fasting state
Liver will try to perform gluconeogensis
HOWEVER
-precursors will be diverted at pyruvate to the production of lactate
-if liver glycogen stores depleted, this can result in hypolycemia
Hypoglycemic effect of fasting and drinking
Can happen to even occasional drinkers, if they happen to drink when their glycogen stores are depleted
Is alcohol a substrate for gluconeogensis?
Nom it is ketogenic but not glucogenic
What do high levels of NADH inhibit?
Oxidation of fatty acids
Net result of inhibition of oxidation of fatty acids due to high levels of NADH
Accumulation of TAG as lipid droplets leading to fatty liver disease, some of the fat is released into the blood stream as VLDLs, which causes hyperlipidemia
The acetyl CoA that is produced from acetate that results from ethanol breakdown
Can not be used in the TCA cycle because of the build up of NADHq
High ratio of acetyl CoA and NADH
Causes the conversion of oxaloacetate back into malate to regenerate NAD+, but since there is already too much fat, that pathway will be inhibited too
What happens to acetyl CoA in ethanol consumption
Tends to get forced into the pathway for ketone syntheiss and ketoacidosis can result
Ethanol effects on nitrogen metabolism
Hyperammonemia and hyperbilirubinemia will result from liver failure
Cytochrome P450 in ethanol metabolism
The induction of cytochrome P450 enzymes and their increased role in ethanol metabolism results in a side effect of free radical production
Acetaldehyde and free radicals
It is a reactive compound that can bind glutathione, depleting glutathione supplies and reducing the cells ability to neutralize free radicals
Free radical mediated damage to the liver
Results in cirrhosis and eventually destruction of the liver
Why do alcoholics suffer from malnutrition?
- alcohol will provide significant calories while providing very little (or no) other nutrients
- the negative effects on the liver, pancreas, and GI tract further increase nutritional deficiencies
What are the two vitamin deficiencies prevalent in alcoholics
- folate deficiency
- thiamine deficiency
Folate deficiency in alcoholics
Results in megaloblastic anemia
Thiamine deficiency in alcoholics
Due to alcohol abuse and causes Wenicke-Korsakoff syndrome divided into two conditions
Wernickes encephalopathy
Reversible early stage of thiamine deficiency
Karsakoff syndrome
Thiamine deficiency
-end stage, brain damage and death
FASD
Any physical or developmental disorders causes by prenatal alcohol exposure
When is the time frame that the most vital organs can be especially damaged in babies?
First 3 months of pregnancy
Alcohol metabolism of pregnant women
Much more depressed compared with that of a non pregnant woman, as estrogen largely inhibit the activity of ADH
What hormone largely inhibits the activity of ADH?
Estrogen
