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MEH Revision > 1 - Oxidative Stress and Alcohol Metabolism > Flashcards

1 - Oxidative Stress and Alcohol Metabolism Flashcards

1
Q

Put the following in order or energy content per gram:

  • Alcohol
  • Protein
  • Fat
  • Carbohydrate
A
  • Fat
  • Alcohol
  • Protein/Carbohydrate
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2
Q

Where is 90% of alcohol metabolised?

Where is the remained metabolised?

A

The Liver

Passively excreted in urine and the breath

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3
Q

Give an overview of how alcohol is metabolised?

A
  • Alcohol is oxidised by alcohol dehydrogenase to acetaldehyde
  • Acetaldehyde converted to acetate by aldehyde dehydrogenase
  • Acetate converted to acetyl-CoA for use in the TCA cycle or fatty acid synthesis
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4
Q

Which cytochrome P450 enzyme can oxidise alcohol?

A

2E1 (CYP2E1)

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5
Q

What enzyme in the brain can oxidise alcohol?

A

Catalase

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6
Q

What is the weekly recommended limit for alcohol consumption?

A

14 units per week over at least 3 days

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7
Q

At what rate is alcohol eliminated by the body?

A

~7g per hour

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8
Q

What type of elimination kinetics does alcohol metabolism show? What does this mean?

A

Zero order kinetics

- Constant rate of metabolism - higher blood alcohol level will not cause the elimination to happen any faster

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9
Q

An intermediate in alcohol metabolism is acetaldehyde. What effects does this have on the body?

A
  • Toxic metabolite

- Accumulation causes hangover (along with dehydration - ADH inhibition) and cirrhosis in the long-term

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10
Q

What molecule is reduced in both conversion of:

  • alcohol to acetaldehyde?
  • acetaldehyde to acetate?
A

NAD+ converted to NADH (NAD+ reduced)

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11
Q

Why is aldehyde dehydrogenase very effective in keeping acetaldehyde toxicity to a minimal level?

A

Very low Km for acetaldehyde (high affinity)

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12
Q

During ……….. and ……….. alcohol consumption, sufficient acetaldehyde accumulates to cause liver damage

A

Prolonged and excessive

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13
Q

What causes fatty liver to occur due to alcohol consumption?

A
  • Increased acetyl-CoA produced
  • Increased synthesis of fatty acids and ketone bodies (also less NAD+ available for B-oxidation of fatty acids)
  • Increased synthesis of triacylglycerols results in fatty deposits in the liver
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14
Q

What causes hypoglycaemia in chronic alcohol consumption?

A
  • Decrease in NAD+/NADH ratio
  • Inadequate NAD+ for conversion of lactate to pyruvate or for glycerol metabolism
  • Less gluconeogenesis in the liver = hypoglycaemia
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15
Q

What causes gout in chronic alcohol consumption?

A
  • Decrease in NAD+/NADH ratio
  • Inadequate NAD+ for conversion of lactate to pyruvate
  • Lactate accumulates in the blood
  • Kidney can’t secrete as much uric acid
  • Urate crystals accumulate in the tissues
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16
Q

What causes lactic acidosis in chronic alcohol consumption?

A
  • Decrease in NAD+/NADH ratio
  • Inadequate NAD+ for conversion of lactate to pyruvate
  • Lactate accumulates in the blood
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17
Q

What is Disulfiram? What does it do?

A
  • Drug used for treatment of chronic alcohol dependence
  • Inhibits aldehyde dehydrogenase
  • If patients drinks alcohol, acetaldehyde accumulates causing an intense ‘hangover’ - classical conditioning to feel sick at the sight of alcohol
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18
Q

Oxidative stress is a balance between cell ……………. (ROS and RNS) and cell ……………… (antioxidants)

A

Damage

Defences

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19
Q

What conditions are commonly related to oxidative stress?

A
  • Alzheimer’s disease
  • Reumatoid arthritis
  • Crohn’s disease
  • COPD
  • Ischaemia/reperfusion injury
  • Cancer
  • Pancreatitis
  • Parkinson’s disease
  • Multiple sclerosis
  • Cardiovascular disease
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20
Q

What is a free radical?

A
  • An atom or molecule with one or more unpaired electrons that is capable of independent existence
  • Very reactive and tend to propagate damage to other molecules
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21
Q

What are the three main reactive oxygen species (ROS)?

Which of these are free radicals?

A
  • Superoxide (O2.-)
  • Hydrogen peroxide (H2O2)
  • Hydroxyl (OH.)

Superoxide and hydroxyl are free radicals. Hydrogen peroxide is a highly reactive, diffusible and toxic molecule.

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22
Q

What ROS radical is the most damaging?

A

Hydroxyl radical (OH.)

  • Reacts strongly with anything
23
Q

What are the two type of reactive nitrogen species (RON)?

A
  • Nitric oxide (NO.)

- Peroxynitrite (ONOO-)

24
Q

How is peroxynitrite formed?

A

Superoxide reacts with nitric oxide

25
Q

What are two ways in which ROS can damage DNA?

A
  • ROS reacts with base (mispairing and mutation)

- ROS reacts with sugar (strand break and mutation on repair)

26
Q

The presence of what molecule in DNA is used as a measurement of oxidative damage?

A
  • 8-oxo-deoxyguanosine

- Formed from deoxyguanosine by ROS and accumulates in DNA

27
Q

What are the two main pathways that ROS can damage proteins?

A
  • ROS fragments protein backbone
  • ROS modifies the amino acids (e.g. carbonyls, hydroxylation, dimerisation, disulphide bonds)

Both lead to loss-of-function and degradation

28
Q

In which level of protein structure do disulphide bonds form?

A

Tertiary structure

29
Q

How do disulphide bonds form?

A
  • bridges formed between thiol groups (-SH) of cysteine residues
30
Q

How can ROS damage lipids?

A
  • Free radicals remove hydrogen from fatty acid chain in lipid membranes forming a lipid radical
  • Reacts with oxygen to for a lipid peroxyl radical
  • Chain reaction with other nearby fatty acids disrupts the lipid membrane
31
Q

Give some endogenous sources of oxidants?

A
  • Electron transport chain
  • Peroxidases
  • Nitric oxide synthases
  • Lipooxygenases
  • NADPH oxidases
  • Xanthine oxidase
  • Monoamine oxidase
32
Q

Give some exogenous sources of oxidants?

A
  • Radiation - cosmic rays, UV, X-rays
  • Pollutants
  • Drugs - Primaquine (anti-malarial)
  • Toxins - Paraquat (herbicide)
33
Q

How does the electron transport chain operate as a source of endogenous free radicals?

A
  • NADH and FAD2H supply e-
  • e- passes through the ETC and reduces oxygen
  • Some electrons escape the chain and react with O2 to form superoxide
34
Q

Describe the action of nitric oxide synthase (NOS).

A
  • Arginine is converted to citrulline and nitric oxide by NOS
35
Q

What are the three types of nitric oxide synthase (NOS)?

A
  • iNOS - inducible - high NO concentrations for toxic effects in phagocytes
  • eNOS - endothelial - signalling in vessels
  • nNOS - neuronal - signalling in neurones
36
Q

Give some functions of nitric oxide.

A

Signalling:

  • Vasodilation
  • Neurotransmission
  • S-nitrosylation

Part of the respiratory burst in phagocytes

37
Q

What is released in the respiratory burst and what does it do?

A
  • Rapid release of superoxide, H2O2 and peroxynitrite from phagocytic cells (e.g. neutrophils and monocytes)
  • Destroy invading bacteria
38
Q

What is chronic granulomatous disease?

A
  • Genetic defect in NADPH oxidase complex of respiratory burst
  • Enhanced susceptibility to bacterial infections (e.g. pneumonia, cellulitis, impetigo)
39
Q

What are the actions of superoxide dismutase and catalase in cellular defence?

A
  • Superoxide dismutase converts superoxide to H2O2

- Catalase converts H2O2 to water and oxygen

40
Q

What is glutathione and what does it do?

A
  • Tripeptide synthesised by the body
  • Protects against oxidative damage
  • Reduced form (GSH) and oxidised form (GSSG)
41
Q

How does glutathione protect against oxidative damage?

A
  • Glutathione is oxidised by glutathione peroxidase
  • e- from GSH reacts with H2O2 to form water
  • Two oxidised GSH molecules for a disulphide bridge - forms GSSG (reduced back to GSH by glutathione reductase)
42
Q

Why is NADPH essential to action of glutathione?

A
  • Electrons from NADPH required for reduction of GSSG back to GSH by glutathione reductase
  • NADPH from pentose phosphate pathway is essential
43
Q

Give an overview of the pentose phosphate pathway.

A
  • Starts with glucose-6-phosphate
  • Source of NADPH and C5-sugars
  • No ATP synthesised
  • Rate limited by G6P dehydrogenase
44
Q

Describe the role of vitamin C and vitamin E in defence against free radicals

A
  • Vitamin E - lipid-soluble antioxidant - protects against lipid peroxidation
  • Vitamin C - water soluble - regenerates reduced form of vitamin E
45
Q

Deficiency in which enzymes can lead to galactosaemia?

A
  • Galactokinase
  • Uridyltransferase
  • UDP-galactose epimerase
46
Q

Galactose is converted to galactitol by ……… …………….

A

Aldose reductase

47
Q

How does galactosaemia contribute to the development of cataracts?

A
  • Deficiency of enzymes in galactosaemia favours conversion of galactose into galactitol (increases osmotic pressure in the eye lens)
  • Increased activity of aldose reductase uses more NADPH = less defence against ROS. The crystallin protein in the eye lens is denatured
48
Q

How does G6PDH deficiency affect GSH?

A
  • A decrease in G6PDH activity limits production of NADPH
  • NADPH is required for reduction of GSSG back to GSH
  • Lower GSH = less protection from oxidative stress
49
Q

What are Heinz bodies?

A
  • Aggregates of cross-linked haemoglobin within red blood cells (induced by H2O2)
  • Bind to the cell membrane altering rigidity, increases effects of mechanical stress on RBCs (haemolysis)
  • Removed by the spleen
50
Q

Heinz bodies are a clinical sign of what condition?

A

G6PDH deficiency

51
Q

At prescribed dosage, how is paracetamol metabolised?

A
  • Conjugated with glucuronide or sulphate in the liver
52
Q

With high levels of paracetamol, how are toxic effects exerted?

A
  • Toxic metabolite NAPQI accumulates
  • NAPQI has direct toxic effects (lipid peroxidation, DNA and protein damage)
  • Glutathione can remove NAPQI but eventually will become depleted
53
Q

What is the antidote to paracetamol overdose and how does it work?

A

Acetylcysteine

- Replenishes glutathione levels to breakdown toxic NAPQI

MEH Revision (4 decks)

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