Alcohol Metabolism

Question 1

What is ethanol used as?

Answer 1

Co-solvent to dissolve several insoluble drugs and serves as a mild sedative

Question 2

What does ethanol bind to?

Answer 2

GABA and N-methyl-D-aspartic acid (NMDA) receptors and modulates their effects

Question 3

What factors affect alcohol absorption?

Answer 3

Gastric emptying rate
Ethanol concentration
Drugs
Rate of consumption

Question 4

How does gastric emptying rate affect alcohol absorption?

Answer 4

If empty stomach then gastric emptying rate increases, increased rate of alcohol absorption, while food (carbs, fats and proteins) does the opposite.

Question 5

What is the first thing that occurs after ethanol is absorbed?

Answer 5

Enters portal vein and travels to the liver, first pass metabolism

Question 6

Where is ethanol metabolized?

Answer 6

Stomach lining and mainly liver

Question 7

What are the three main pathways for ethanol metabolism in hepatocytes?

Answer 7

Alcohol dehydrogenase, located at cytosol

Microsomal ethanol-oxidising system (MEOS), located at endoplasmic reticulum

Catalase pathway, located in peroxisomes

Question 8

What do all alcohol metabolism pathways generate?

Answer 8

Acetaldehyde, a highly toxic metabolite

Question 9

What are the effects of acetaldehyde?

Answer 9

Carcinogenic and Toxic effects

Question 10

Explain the carcinogenic effects of acetaldehyde.

Answer 10

Associated with increased risk of mouth, throat, and oesophagus cancer.

Slowing down DNA replication

Inhibits DNA repair

Question 11

Explain toxic effects of acetaldehyde.

Answer 11

Toxic to various organs: heart, lungs, nervous system
Disrupts normal cellular functions and contribute to tissue damage

Question 12

What is the ADH pathway of alcohol metabolism?

Answer 12

Reversible step: Entail to Acetaldehyde (alcohol dehydrogenase)

Acetaldehyde to Acetate (aldehyde dehydrogenase)

Question 13

Where do the different steps of the ADH pathway take place?

Answer 13

ADH in cytosol
ALSH in mitochondria

Question 14

What happens to the acetate during the ADH pathway?

Answer 14

It turns into acetyl CoA, with the enzyme acetyl-CoA synthase

Question 15

What kind of order does ethanol elimination follow?

Answer 15

Zero-order kinetics

Question 16

What is zero-order kinetics?

Answer 16

The rate of metabolism is not dependent on the concentration of the substance

Question 17

What happens to the substance during zero-order kinetics?

Answer 17

A constant amount of the substance is metabolised per unit of time.

Question 18

How does alcohol dehydrogenase operate when saturated with ethanol?

Answer 18

Operates at a constant rate

Question 19

What kind of enzyme is ADH?

Answer 19

NAD+-dependent cytoplasmic enzyme

Question 20

What is the purpose of ADH?

Answer 20

To oxidize ethanol to acetaldehyde

Question 21

How many isozymes of ADH are there?

Answer 21

6

Question 22

What happens if ADH is mutated in some individuals?

Answer 22

Slower alcohol metabolism and even small volumes of alcohol may produce symptoms of intoxication

Question 23

What kind of enzyme is ALDH?

Answer 23

A mitochondrial NAD+-dependent enzyme

Question 24

What is the function of ALDH?

Answer 24

To oxidize acetaldehyde to acetate

Question 25

What is the role of ALDH?

Answer 25

Maintain low blood levels of acetaldehyde during alcohol oxidation

Question 26

What are the different classes of ADH isozymes?

Answer 26

Class I: ADH1A, ADH1B, ADH1C Class II: ADH4 Class III: ADH3

Question 27

What does a lower Km value mean?

Answer 27

Higher affinity of enzyme for substrate

Question 28

Which are the two ALDH enzymes that metabolise acetaldehyde?

Answer 28

Cytosolic ALDH 1 and mitochondrial ALDH2

Question 29

What causes Asian flush syndrome?

Answer 29

A genetic mutation known as the ALDH2*2 allele resulting in a less active or non-functional form of the ALDH2 enzyme.

Question 30

What does the accumulation of toxic acetaldehyde lead to?

Answer 30

Increased heart rate, facial flushing, nausea, discomfort and headache.

Question 31

What is MEOS?

Answer 31

An alternative pathway for the metabolism of ethanol in the liver.

Question 32

What causes MEOS to become more active?

Answer 32

Chronic or heavy alcohol consumption

Question 33

Where is MEOS located?

Answer 33

In the endoplasmic reticulum of hepatocytes

Question 34

What is the primary enzyme responsible for the MEOS pathway?

Answer 34

Cytochrome P450 2E1

Question 35

What is the function of CYP2E1?

Answer 35

To metabolize ethanol into acetaldehyde

Question 36

What also occurs during the MEOS pathway?

Answer 36

Reactive oxygen species (ROS) and free radicals are produced as byproducts

Question 37

What do ROS and free fatty acids lead to?

Answer 37

Contribute to oxidative stress and damage to liver cells

Question 38

What is catalase?

Answer 38

An enzyme particularly in the peroxisomes

Question 39

What is the function of the catalase pathway?

Answer 39

Breakdown of hydrogen peroxide into water and oxygen Catalyzes the conversion of ethanol directly to acetaldehyde and acetate

Question 40

What other enzymes have similar functions to catalase?

Answer 40

ADH and ALDH

Question 41

What is the minor role of of the catalase pathway?

Answer 41

Metabolizes ethanol in other tissues other than the liver

Question 42

Which enzyme (s) are the most responsible for the metabolism of ethanol?

Answer 42

ADH and ALDH

Question 43

How is ethanol non-oxidatively metabolised?

Answer 43

Fatty acid ethyl ester synthase Phospholipase D

Question 44

What molecules are produced when the reaction is catalysed by FAEE synthase?

Answer 44

Fatty acid ethyl esters which then leads to tissue injury

Question 45

What is formed when a reaction is catalysed by PLD?

Answer 45

Phospholipid known as phosphatidyl ethanol which interferes with PLD-dependent signalling

Question 46

What are the consequences of biomedical pathways triggered by alcohol metabolism? And why do they occur?

Answer 46

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

Question 47

What causes the dysregulation of glycolysis?

Answer 47

Increase levels of NADH after GADP is converted to 1,3-bisphosphoglycerate

Question 48

What causes lactic acidosis?

Answer 48

Increase in NADH after pyruvate is converted into lactate

Question 49

What causes the inhibition of gluconeogenesis and hypoglycemia?

Answer 49

Deficiency of pyruvate --> inadequate formation of oxaloacetate That results in suppression of gluconeogenesis which leads to hypoglycaemia

Question 50

Why is there an effect on the TCA cycle?

Answer 50

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

Question 51

What is the effect on the TCA cycle?

Answer 51

It is suppressed

Question 52

What is the effect on fatty acid synthesis?

Answer 52

Fatty acid synthesis increases and so does oxidation

Question 53

Why is there an increase in fatty acid synthesis?

Answer 53

Increase in acetyl CoA which causes an increase in malonyl CoA and thus increase in fatty acid synthesis.

Question 54

What causes fatty liver disease?

Answer 54

Increase in malonyl CoA which inhibits fatty acid catabolism and thus there is triglyceride accumulation which leads to hepatosteasis

Question 55

What is cirrhosis?

Answer 55

Long-term damage characterized by replacement of normal liver tissue with scar tissues

Question 56

What leads to liver damage?

Answer 56

Accumulation of excess fat in the liver due to increased synthesis of fat

Question 57

What happens if there is liver damage?

Answer 57

Enlarge adipose cells choke off nutrient and O2 supply to the liver cells Engorged adipose cells burst and die Scar tisse

Question 58

What are some causes of cirrhosis?

Answer 58

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