Alcohol Metabolism Flashcards
What is ethanol used as?
Co-solvent to dissolve several insoluble drugs and serves as a mild sedative
What does ethanol bind to?
GABA and N-methyl-D-aspartic acid (NMDA) receptors and modulates their effects
What factors affect alcohol absorption?
Gastric emptying rate
Ethanol concentration
Drugs
Rate of consumption
How does gastric emptying rate affect alcohol absorption?
If empty stomach then gastric emptying rate increases, increased rate of alcohol absorption, while food (carbs, fats and proteins) does the opposite.
What is the first thing that occurs after ethanol is absorbed?
Enters portal vein and travels to the liver, first pass metabolism
Where is ethanol metabolized?
Stomach lining and mainly liver
What are the three main pathways for ethanol metabolism in hepatocytes?
Alcohol dehydrogenase, located at cytosol
Microsomal ethanol-oxidising system (MEOS), located at endoplasmic reticulum
Catalase pathway, located in peroxisomes
What do all alcohol metabolism pathways generate?
Acetaldehyde, a highly toxic metabolite
What are the effects of acetaldehyde?
Carcinogenic and Toxic effects
Explain the carcinogenic effects of acetaldehyde.
Associated with increased risk of mouth, throat, and oesophagus cancer.
Slowing down DNA replication
Inhibits DNA repair
Explain toxic effects of acetaldehyde.
Toxic to various organs: heart, lungs, nervous system
Disrupts normal cellular functions and contribute to tissue damage
What is the ADH pathway of alcohol metabolism?
Reversible step: Entail to Acetaldehyde (alcohol dehydrogenase)
Acetaldehyde to Acetate (aldehyde dehydrogenase)
Where do the different steps of the ADH pathway take place?
ADH in cytosol
ALSH in mitochondria
What happens to the acetate during the ADH pathway?
It turns into acetyl CoA, with the enzyme acetyl-CoA synthase
What kind of order does ethanol elimination follow?
Zero-order kinetics
What is zero-order kinetics?
The rate of metabolism is not dependent on the concentration of the substance
What happens to the substance during zero-order kinetics?
A constant amount of the substance is metabolised per unit of time.
How does alcohol dehydrogenase operate when saturated with ethanol?
Operates at a constant rate
What kind of enzyme is ADH?
NAD+-dependent cytoplasmic enzyme
What is the purpose of ADH?
To oxidize ethanol to acetaldehyde
How many isozymes of ADH are there?
6
What happens if ADH is mutated in some individuals?
Slower alcohol metabolism and even small volumes of alcohol may produce symptoms of intoxication
What kind of enzyme is ALDH?
A mitochondrial NAD+-dependent enzyme
What is the function of ALDH?
To oxidize acetaldehyde to acetate
What is the role of ALDH?
Maintain low blood levels of acetaldehyde during alcohol oxidation
What are the different classes of ADH isozymes?
Class I: ADH1A, ADH1B, ADH1C
Class II: ADH4
Class III: ADH3
What does a lower Km value mean?
Higher affinity of enzyme for substrate
Which are the two ALDH enzymes that metabolise acetaldehyde?
Cytosolic ALDH 1 and mitochondrial ALDH2
What causes Asian flush syndrome?
A genetic mutation known as the ALDH2*2 allele resulting in a less active or non-functional form of the ALDH2 enzyme.
What does the accumulation of toxic acetaldehyde lead to?
Increased heart rate, facial flushing, nausea, discomfort and headache.
What is MEOS?
An alternative pathway for the metabolism of ethanol in the liver.
What causes MEOS to become more active?
Chronic or heavy alcohol consumption
Where is MEOS located?
In the endoplasmic reticulum of hepatocytes
What is the primary enzyme responsible for the MEOS pathway?
Cytochrome P450 2E1
What is the function of CYP2E1?
To metabolize ethanol into acetaldehyde
What also occurs during the MEOS pathway?
Reactive oxygen species (ROS) and free radicals are produced as byproducts
What do ROS and free fatty acids lead to?
Contribute to oxidative stress and damage to liver cells
What is catalase?
An enzyme particularly in the peroxisomes
What is the function of the catalase pathway?
Breakdown of hydrogen peroxide into water and oxygen
Catalyzes the conversion of ethanol directly to acetaldehyde and acetate
What other enzymes have similar functions to catalase?
ADH and ALDH
What is the minor role of of the catalase pathway?
Metabolizes ethanol in other tissues other than the liver
Which enzyme (s) are the most responsible for the metabolism of ethanol?
ADH and ALDH
How is ethanol non-oxidatively metabolised?
Fatty acid ethyl ester synthase
Phospholipase D
What molecules are produced when the reaction is catalysed by FAEE synthase?
Fatty acid ethyl esters which then leads to tissue injury
What is formed when a reaction is catalysed by PLD?
Phospholipid known as phosphatidyl ethanol which interferes with PLD-dependent signalling
What are the consequences of biomedical pathways triggered by alcohol metabolism? And why do they occur?
They occur because there is an increase in NADH and Acetyl CoA and a decrease in NAD+ to NADH
Consequences:
- Glycolysis dysregulation
- LActic acidosis
- Inhibition of gluconeogenesis and hypoglycemia
- Dysregulation of TCA cycle
- Effect on fatty acid synthesis and oxidation
What causes the dysregulation of glycolysis?
Increase levels of NADH after GADP is converted to 1,3-bisphosphoglycerate
What causes lactic acidosis?
Increase in NADH after pyruvate is converted into lactate
What causes the inhibition of gluconeogenesis and hypoglycemia?
Deficiency of pyruvate –> inadequate formation of oxaloacetate
That results in suppression of gluconeogenesis which leads to hypoglycaemia
Why is there an effect on the TCA cycle?
Affected at the level of malate dehydrogenase because there is an increase of NADH in mitochondria which will shift the reaction backwards leading to increase of malate
What is the effect on the TCA cycle?
It is suppressed
What is the effect on fatty acid synthesis?
Fatty acid synthesis increases and so does oxidation
Why is there an increase in fatty acid synthesis?
Increase in acetyl CoA which causes an increase in malonyl CoA and thus increase in fatty acid synthesis.
What causes fatty liver disease?
Increase in malonyl CoA which inhibits fatty acid catabolism and thus there is triglyceride accumulation which leads to hepatosteasis
What is cirrhosis?
Long-term damage characterized by replacement of normal liver tissue with scar tissues
What leads to liver damage?
Accumulation of excess fat in the liver due to increased synthesis of fat
What happens if there is liver damage?
Enlarge adipose cells choke off nutrient and O2 supply to the liver cells
Engorged adipose cells burst and die
Scar tisse
What are some causes of cirrhosis?
Chronic alcohol abuse
Chronic viral hepatitis
Fat accumulation in the liver
Iron buildup
Cystic fibrosis
Destruction of bile ducts
Hardening and scarring of bile ducts
