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Metabolism, Endocrinolgy & Haematology > Session 1 Lecture 1 : Oxidative stress and Alcohol Metabolism > Flashcards

Session 1 Lecture 1 : Oxidative stress and Alcohol Metabolism Flashcards

1
Q

Order the following in terms of energy content from High to Low:

Protein, Alcohol, Carbohydrate, Fat

A

Fat - 37 KJ/g

Alcohol - 29 KJ/g

Protein - 17 KJ/g

Carbohydrate - 17 KJ/g

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2
Q

Describe how alcohol is metabolised

A

Alcohol —–> Acetaldehyde ——–> Acetate

  • alcohol oxidised into acetaldehyde by alcohol dehydrogenase
  • acetaldehyde oxidised into acetate by aldehyde dehydrogenase
  • NAD+ is converted into NADH
  • acetate converted to acetyl-CoA and used in TCA cycle or for the fatty acid synthesis
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3
Q

Explain how alcohol can cause liver damage

A
  • Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde to accumulate causing liver damage
  • Excess NADH and Acetyl-CoA lead to changes in liver metabolism
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4
Q

The metabolic response to chronic alcohol consumption

How can lactic acidosis occur due to a decrease in the NAD+/NADH ratio?

A
  • Inadequate NAD+ for the conversion of lactate to pyruvate
  • lactate accumulates in the blood
  • lactic acidosis
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5
Q

The metabolic response to chronic alcohol consumption

How can Gout occur due to a decrease in the NAD+/NADH ratio?

A
  • Inadequate NAD+ for the conversion of lactate to pyruvate
  • lactate accumulates in the blood
  • kidney’s ability to excrete uric acid reduced
  • urate crystals accumulate in tissues producing gout
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6
Q

The metabolic response to chronic alcohol consumption

How can Hypoglycaemia occur due to a decrease in the NAD+/NADH ratio?

A
  • Inadequate NAD+ for glycerol metabolism
  • Inadequate NAD+ for the conversion of lactate to pyruvate
  • deficit in gluconeogenesis
  • Hypoglycaemia
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7
Q

The metabolic response to chronic alcohol consumption

How can Fatty liver occur due to a decrease in the NAD+/NADH ratio?

A
  • Inadequate NAD+ for fatty acid oxidation
  • Increased synthesis of triacylglycerol
  • lower lipoprotein synthesis
  • fatty liver
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8
Q

The metabolic response to chronic alcohol consumption

How can Fatty liver occur due to an increase in Acetyl-CoA?

A
  • increased synthesis of fatty acids and ketone bodies
  • Increased synthesis of triacylglycerol
  • lower lipoprotein synthesis
  • fatty liver
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9
Q

Explain the mechanisms of action of Disulfiram

A
  • Disulfiram is used to treat chronic alcohol dependence
  • Disulfiram inhibits aldehyde dehydrogenase
  • consumption of alcohol whilst taking this drug will cause a build-up of acetaldehyde and therefore producing nausea-like symptoms
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10
Q

What is oxidative stress?

A

Oxidative stress occurs when the production of ROS is excessive or antioxidants levels are low in the cell therefore balance is shifted in favour of ROS.

ROS= reactive oxygen species

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11
Q

Describe the production of superoxide radicals

A

Electrons transferred to molecular oxygen

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12
Q

State other ROS (Reactive oxygen species) and how they are formed

A
  • Hydrogen peroxide(H2O2): produced by adding 2 H+ and 1 e- to superoxide. Though not a free radical, it can react with Fe2+ to create free radicals
  • Hydroxyl radical(OH)(superscript dot): produced by adding 1e- and 1H+ to hydrogen peroxide. Most damaging free radical and can damage DND, lipids and proteins.
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13
Q

State RNS (reactive nitrogen species) and how they are formed

A
  • Nitric oxide (NO) superscript dot

- Peroxynitrite(ONOO-): nitric oxide + superoxide powerful oxidant that can damage cell

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14
Q

How can ROS damage DNA?

A
  • ROS reacts with DNA
  • DNA damage
  • Failure in repair can lead to mutation
  • Can lead to cancer
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15
Q

State the two main types of damage ROS can do to DNA

A
  • ROS reacts with base: modified base can lead to mispairing and mutation
  • ROS reacts with sugar(ribose or deoxyribose): can cause strand break and mutation on repair
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16
Q

How can ROS damage proteins?

A
  • affect the backbone which can lead to fragmentation and then protein degradation
  • affect side-chain —–> change in protein structure —–> gain or loss of function and if latter this will lead to protein degradation
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17
Q

How can ROS damage Lipids?

A
  • Lipid peroxidation
  • occurs in the cell membrane
  • initiation when free radical takes hydrogen from polyunsaturated fatty acid in membrane
  • chain reactions of new lipid radicals formed, extracting hydrogen from nearby fatty acids
  • cell membrane compromised and integrity fails as the hydrophobic environment of the bilayer is disrupted
18
Q

Endogenous sources of biological oxidants (ROS&RNS)

A
  • electron transport chain
  • nitric oxide synthases (NOS)
  • NADPH oxidases(respiratory burst)
19
Q

Exogenous sources of biological oxidants (ROS&RNS)

A
  • Radiation e.g Cosmic rays, UV light, X-rays
  • Pollutants
  • Drugs e.g primaquine (anti-malarial)
  • Toxins e.g paraquat (herbicides)
20
Q

How does the electron transport chain act as a source of ROS?

A
  • occurs in mitochondria
  • NADH and FADH2 supply electrons
  • electrons pass through ETC and reduce oxygen(last electron carrier) to form water
  • sometimes electrons escape the chain and react with dissolved molecular oxygen to form superoxide
21
Q

How does Nitric Oxide synthase(NOS) act as a source of RNS?

A
  • Arginine is converted into citrulline via the enzyme nitric oxide synthase
  • the by-product of this reaction is nitric oxide
22
Q

State the 3 types of nitric oxide synthases

A
  • iNOS: inducible nitric oxide synthase. produces high nitric oxide conc in phagocytes for direct toxic effects
  • eNOS: endothelial nitric oxide synthase (signalling)
  • nNOS: neuronal nitric oxide synthase (signalling)
23
Q

Roles of Nitric Oxide in the body

A
  • toxic effects at high levels

- signalling molecule for vasodilation, neurotransmission and S-Nitrosylation

24
Q

How does NADPH oxidase act as a source of ROS?

A
  • causes respiratory burst which is part of the antimicrobial defence system that destroys invading bacteria
  • rapidly produces a release of ROS (superoxide and hydrogen peroxide) when stimulated
  • transfers electrons from NADPH to molecular oxygen to generate superoxide radicals
25
Q

Outline defences against reactive oxygen species

A
  • Superoxide dismutase (SOD)
  • Catalase
  • Glutathione(tripeptide)
  • NADPH
  • Free radical scavengers
26
Q

How does Superoxide dismutase (SOD) protect against ROS?

A

Converts superoxide to hydrogen peroxide and oxygen

27
Q

How does Catalase protect against ROS?

A

Converts hydrogen peroxide to water and oxygen

28
Q

How does Glutathione(tripeptide) protect against ROS?

A
  • donates an electron to ROS: H2O2 -> H2O

- forms a disulphide bond with another GSH to form GSSG via the enzyme glutathione peroxidase

29
Q

How does NADPH protect against ROS?

A
  • maintains GSH (glutathione) levels by reducing GSSG to GSH (reduced form) via the enzyme glutathione reductase.
  • reduced GSH is available to donate an electron to ROS thus removing them
30
Q

How do Free radical scavengers protect against ROS?

A

reduce free radical damage by donating 1H+ and its electron to free radicals in a nonenzymatic reaction

31
Q

Examples of Free radical scavengers

A
  • Vitamin E: lipid-soluble antioxidant. Important for protection against lipid peroxidation
  • Vitamin C: water-soluble antioxidant. An important role in regenerating reduced form of vit E
  • Carotenoids
  • Flavanoids
  • Melatonin
  • Uric acid
32
Q

State 2 clinical relevance of Oxidative stress

A
  • Galactosaemia

- G6PDH deficiency

33
Q

What occurs in Galactosaemia? How does it lead to oxidative stress?

A
  • Deficiency in transferase or kinase enzyme
  • build up of galctose
  • increased activity of enzyme aldose reductase to convert galactose into galactitol which uses up NADPH+
  • low levels of NADPH anitoxidants
34
Q

Symptoms of Galactosaemia

A
  • Cataracts
  • Vomiting
  • Renal failure
  • Hypoglycaemia
  • Seizure + Brain damage
35
Q

How do Cataracts form?

A
  • low levels of NADPH+ compromises defences against ROS damage
  • crystallin protein in the lens of eye denatured
  • cataracts
36
Q

What occurs in G6PDH deficiency? How does it lead to oxidative stress?

A
  • lack of glucose 6 phosphate dehydrogenase enzyme
  • used in the pentose phosphate pathway to convert glucose 6 phosphate into 6 phosphate gluconate producing NADPH in the process
  • reduced activity of G6PDH limits amount of NADPH
  • low levels of antioxidants NADPH
37
Q

What are the clinical signs of having a G6PDH deficiency?

A
  • Haemolysis —> haemolytic anaemia

- Jaundice

38
Q

How does Haemolysis occur?

A
  • GSH levels not maintained as NADPH levels are decreased
  • less protection from oxidative stress
  • hydrogen peroxide (ROS) damages lipids and protein
  • protein damage leads to aggregation of crosslinked haemoglobin via inappropriate disulfide bonds and these are called Heinz Bodies
  • these reduce number of functioning RBC and therefore haemolysis
39
Q

How does Jaundice occur?

A
  • High bilirubin levels
  • bilirubin is a yellow byproduct of the breakdown of damaged RBC produced from the metabolism of the haem group of haemoglobin in the spleen
  • excreted in bile and urine
40
Q

What is the toxic metabolite that accumulated when levels of paracetamol are high?

A

NAPQI
N-acetyl-p-benzoquinone imine

-causes oxidative damage to liver cells

41
Q

What is the treatment given for over usage of paracetamol?

A

Acetylcysteine

-works by replenishing glutathione levels

Metabolism, Endocrinolgy & Haematology (2 decks)

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