Sesh 3- Alcohol Metabolism and Oxidative Stress

Question 1

What is the major site of alcohol metabolism?

Answer 1

The liver

Question 2

Which 2 enzymes are involved in alcohol metabolism?

Answer 2

1. Alchohol dehydrogenase

2. Aldehyde dehydrogenase

Question 3

What is the end product of normal alcohol metabolism?

Answer 3

Acetyl CoA

Question 4

What is the toxic metabolite in alcohol metabolism?

Answer 4

Acetaldehyde

Question 5

Excessive alcohol consumption _______ NADH levels.

Answer 5

Increases

Question 6

How can excessive consumption of alcohol lead to lactic acidosis?

Answer 6

• Uses up NAD+, so less NAD+ available to help convert lactate to pyruvate
• Lactate accumulates in the blood

Question 7

Why does excessive alcohol consumption lead to increased fatty acid and ketone body production?

Answer 7

Leads to increased synthesis of acetyl CoA, but this cannot be oxidised due to inadequate NAD+, so is converted to fatty acids and ketone bodies.

Question 8

How can excessive alcohol consumption lead to oedema?

Answer 8

• Acetaldehyde causes hepatocyte damage.
• Hepatocytes then less able to synthesise albumin, leading to reduced oncotic pressure of plasma.
• Therefore increased filtration into interstitium at the capillary.

Question 9

Why is a fatty liver a result of excess alcohol consumption?

Answer 9

• Damaged hepatocytes cannot produce lipoproteins to transport lipids
• Increased fatty acids lead to increased lipid synthesis- cannot be transported so accumulate in liver

Question 10

What is the drug used to treat alcohol dependence, and how does it work?

Answer 10

• Disulfiram.
• Inhibits aldehyde dehydrogenase, so if patient drinks alcohol, acetaldehyde will accumulate and cause ‘hangover’ symptoms

Question 11

What are the recommended alcohol intake limits for men and women?

Answer 11

14 units per week spread over at least 3 days for men and women.

Question 12

What is a free radical?

Answer 12

Any atom, ion or molecule with an unpaired electron and is capable of free existence.

Question 13

List 3 reactive oxygen species.

Answer 13

1. Superoxide
2. Hydrogen peroxide
3. Hydroxyl radical

Question 14

What is the most damaging free radical?

Answer 14

The hydroxyl radical.

Question 15

Give 2 reasons why mitochondrial DNA is more susceptible than nuclear DNA to ROS damage.

Answer 15

1. Close to inner mitochondrial membrane where ROS are formed
2. Not protected by histones

Question 16

What is the reaction of ROS with lipids called?

Answer 16

Lipid peroxidation

Question 17

What 3 things can ROS damage?

Answer 17

1. DNA
2. Protein
3. Lipids

Question 18

Why does lipid peroxidation by free radicals result in loss of membrane integrity?

Answer 18

• Free radical extracts electron from fatty acid in the membrane to produce a lipid radical
• This lipid radical can then take electron from a neighbouring fatty acid to form further lipid radicals
• Chain reaction

Question 19

How can superoxide radicals be formed endogenously?

Answer 19

Stray electrons can escape the electron transport chain to react with oxygen.

Question 20

Which membrane-bound enzyme complex is involved in free radical production during the respiratory burst?

Answer 20

NADPH oxidase

Question 21

In what disease is there a genetic defect in NADPH oxidase?

Answer 21

Chronic granulomatous disease (a primary immune deficiency).

Question 22

Name 2 enzymes important in endogenous protection against oxidative damage.

Answer 22

1. Superoxide dismutase

2. Catalase

Question 23

How does glutathione protect against oxidative damage?

Answer 23

• Thiol group of cysteine donates an electron to ROS

- GSH then forms a disulphide bond with another GSH to become stable

Question 24

Which enzyme catalyses the oxidation of glutathione?

Answer 24

Glutathione peroxidase

Question 25

Name 2 vitamins that protect against oxidative damage.

Answer 25

Vit E and C

Question 26

Which vitamin is especially important in protecting against lipid peroxidation and why?

Answer 26

Vitamin E, because it's lipid soluble

Question 27

Why are ROS defences compromised in galactosaemia?

Answer 27

- Excess galactose is converted to galactitol by aldose reductase. - This uses up NADPH - Less NADPH to convert oxidised glutathione back to its reduced active form

Question 28

Why can cataracts form in galactosaemia?

Answer 28

- Reduced ROS protection, so disulphide bonds form in crystallin protein in lens - Glycosylation of lens proteins (small contribution)

Question 29

Why are patients with glucose-6-phosphate dehydrogenase deficiency susceptible to ROS damage?

Answer 29

-Cannot convert glucose-6-phosphate to ribose in pentose phosphate pathway, so cannot regenerate NADPH needed to convert glutathione back to its active form.

Question 30

Give 2 signs on a blood film of glucose-6-phosphate dehydrogenase deficiency.

Answer 30

1. Heinz bodies | 2. Blister cells

Question 31

Name 2 endogenous sources of free radicals.

Answer 31

1. Electron transport chain | 2. NADPH oxidase in respiratory burst

Question 32

At doses over 10g, what toxic metabolite is formed from paracetamol?

Answer 32

NAPQI

Question 33

How does NAPQI cause oxidative damage to hepatocytes?

Answer 33

1. Direct toxic effects | 2. Conjugates with glutathione, so reduced glutathione to protect against oxidative damage

Question 34

Which drug can be used to treat paracetamol overdose, and how does it work?

Answer 34

N-acetylcysteine replenishes glutathione levels.