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MEH > 1.1 - Oxidative Stress > Flashcards

1.1 - Oxidative Stress Flashcards

1
Q

Where is alcohol metabolised?

A

90% metabolised in the liver
The rest is excreted passively on breath and in urine.
Small amounts oxidises by cytochrome P450 2E1 enzyme or by catalase in the brain.

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2
Q

What is the recommended alcohol limit?

A

14 units/ week over 3 days for men and women

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3
Q

What is a unit of alcohol?

A

8g of pure alcohol. 1 unit is equivalent to half a pint of beer or a small glass of wine.

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4
Q

What is the rate of alcohol metabolism?

A

1 unit per hour at a constant linear rate (follows zero order kinetics.

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5
Q

How is ethanol transformed to acetate?

A
  1. Alcohol reduced by alcohol dehydrogenase to produce acetaldehyde
  2. Acetaldehyde reduced by aldehyde dehydrogenase to acetate
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6
Q

What is reduced in the metabolism of alcohol?

A

NAD+ reduced in both steps of alcohol metabolism to form NADH.

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7
Q

What causes a hangover after excessive alcohol consumption?

A

Accumulation of toxic acetaldehyde

Dehydration

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8
Q

Why can alcohol consumption lead to dehydration?

A

Ethanol inhibits the secretion of antidiuretic hormone from the posterior pituitary

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9
Q

Alcohol dehydrogenase as a low specificity. What does this mean?

A

It works on a large variety of substrates.

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10
Q

Why is it important that aldehyde dehydrogenase has a low Km for acetaldehyde?

A

A low Km means it has a high affinity as Km is the concentration of substrate which permits the enzyme to achieve half Vmax.
It is important that the infinity is high so that acetaldehyde quickly is metabolised by aldehyde dehydrogenase as it is toxic. This keeps the levels of acetaldehyde low (10^-7mol.L^-1)

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11
Q

How is acetate used in the body?

A

Combined with coenzymeA to form acetyl-CoA. This reaction requires energy and ATP is broken down to AMP and pyrophosphate.

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12
Q

What clinical conditions are associated with excessive alcohol consumption?

A 
Liver damage
Gout
Lactic acidosis
Hypoglycaemia
Damage to GI tract
Chronic Pancreatitis
indirect affect to CNS and mental health.
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13
Q

What 3 factors of alcohol consumption contribute to liver damage?

A

Decrease in NAD+/NADH ratio
Increased acetyl-CoA
Damage to liver cells by toxic effects of acetaldehyde.

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14
Q

How is a decrease in NAD+/NADH ratio harmful for the body?

A

Contributes to gout, lactic acidosis and hypoglycaemia.
NAD+ levels too low for use in:
-conversion of lactate to pyruvate. Lactate accumulate in blood causing lactic acidosis
- lactate accumulation in blood reduces the kidneys ability to excrete uric acid. Urate crystals accumulate in joint tissues, producing gout
- decreased glycerol metabolism due to liver damage. Decreased lactate and glycerol metabolism means decreased gluconeogenesis resulting in hypoglycaemia.

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15
Q

How is increased acetyl-CoA levels harmful for the body?

A

Due to low NAD+ levels, acetyl-CoA is not oxidised. To stop accumulation, it is instead used in the synthesis of fatty acids and ketone bodies. Production of keto bodies may cause keto acidosis
Inadequate NAD+ levels lead to fatty acids being converted to triglycerides as beta oxidation cannot take place.
Triglycerides are not transported as there is lower lipoprotein synthesis in the liver. Fatty liver.

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16
Q

How do liver cells become damaged by alcoholism?

A

Excessive ethanol intake results in build up of toxic metabolite acetaldehyde. This metabolite damages liver cells.

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17
Q

What are the clinical consequences of damaged liver cells?

A
  • Jaudice. Liver cells cannot take up and conjugate bilirubin. Levels of bilirubin increase in the blood resulting in hyperbilirubinaemia.
  • Damaged liver cells cannot produce urea well resulting in hyperammonaemia and increased glutamine levels.
  • Oedema - decreased synthesis of albumin in liver
  • increased blood clotting time. Decreased production of clotting factor in the liver
  • fatty liver. Decreased production of lipoproteins, lipids synthesised in the liver cannot be transported.
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18
Q

How can we test for liver damage?

A

Damaged liver cells have a leaky plasma membrane, resulting in loss of enzymes from liver cells. These can be tested for in the blood as an indicator of liver damage.

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19
Q

What are the indirect consequences of excessive alcohol consumption?

A

Alcohol is expensive so dependence may cause financial problems
Effects on the CNS
Associated with poor dietary habit

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20
Q

How does alcohol affect the GI tract?

A

Loss of appetite
Diarrhoea
Impaired absorption of some nutrients

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21
Q

Alcohol results in chronic pancreatitis. How does this present?

A

Pain in abdomen and back. Malabsorption of food leads to insufficient production of pancreatic enzymes leading to weight loss. Diabetes may develop if there is damage to beta cells, resulting in hyperglycaemia and glucouria.

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22
Q

How is alcohol dependence treated?

A

Disulfram and additional support (CBT)

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23
Q

How does disulfram work?

A

Inhibits aldehyde dehydrogenase, allowing acetaldehyde to build up in blood if alcohol is consumed. This results in nausea.

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24
Q

What diseases are associated with oxidative stress?

A 
Cardiovascular disease
Alzheimer’s disease
Rheumatoid arthritis
Crohn’s disease
COPD
Ischaemia 
Cancer
Pancreatitis
Parkinson’s disease
Multiple sclerosis
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25
Q

What is oxidative stress?

A

Oxidative damage to cells resulting when cellular attack from oxidants is greater than cellular antioxidant defences.

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26
Q

How are reactive nitrogen species involved in inflammation?

A

Enzyme inducible nitric oxide synthetase (iNOS) produced nitric oxide which is converted to peroxynitrtae radicals.

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27
Q

What is a free radical?

A

A molecule containing one or more unpaired electrons in an orbital.

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28
Q

How do free radicals propagate damage?

A

Very reactive and propagate damage by acquiring electrons form other molecules, generating a second free radical in the process.

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29
Q

How are free radicals produced?

A

Ionising radiation
Aging
Toxins (herbicide paraquat)

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30
Q

How is superoxide produced?

A

When biradical oxygen molecule is reduced prematurely by accepting an singular electron in the ETC, superoxide is formed. These electrons escape the ETC too soon

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31
Q

What are the three ROS?

A

Superoxide
Hydrogen peroxide
Hydroxyl radical

32
Q

How is hydrogen peroxide produced?

A

Superoxide accepts 2H+ and an electron to form hydrogen peroxide

33
Q

Is hydrogen peroxide a free radical?

A

H2O2 is not a free radical, but is very reactive and can result in the formation of more free radicals.

34
Q

How is a hydroxyl radical produced?

A

Hydrogen peroxide reacts with H+ and an electron to produce water and a hydroxyl radical.

35
Q

How is peroxynitrite produced?

A

Nitric oxide radical reacts with superoxide to form peroxynitrite

36
Q

What is peroxynitite?

A

Not a free radical but highly reactive. Powerful oxidant formed from nitric oxide radical and superoxide, damages cells.

37
Q

What structures are damaged by ROS?

A

DNA
Proteins
Lipid membranes

38
Q

How is DNA damaged by free radicals?

A
  1. ROS react with base. Modified base leads to misplaying and mutation. Failure to repair results in cancer.
  2. ROS reacts with sugar (ribose or deoxyribose). Can cause strand break and mutation on repair.
39
Q

Why is mitochondrial DNA susceptible to ROS damage?

A

ROS formed near the inner mitochondrial membrane and mitochondrial DNA is not protected by histones.

40
Q

How can we measure ROS damage to DNA?

A

Amount of oxidised guanine base in cells can be used as a measurement of oxidative damage.

41
Q

How does ROS damage proteins?

A

ROS can take an electron from cysteine residues ad form inappropriate disulphide bonds. This modifies structure leading to degradation or change of function.

42
Q

How are disulphide bonds formed?

A

They are formed between the thiol groups of cysteine residues when they are oxidised

43
Q

What are heinz bodies?

A

Insoluble precipitates aggregates within red blood cells. They are composed denatured haemoglobin. Heinz bodies lead to premature RBC destruction and haemolysis

44
Q

How are Heinz bodies formed?

A

When haemoglobin becomes cross linked due to the formation of inappropriate disulphide bonds. May be caused by ROS.

45
Q

What is lipid peroxidation?

A

A propagating series of oxidation reactions along lipid molecules in the lipid membrane initiated by ROS.

46
Q

How does lipid peroxidation occur?

A

Initiation - Hydroxyl radical reacts with an unsaturated lipid forming a lipid radical.

Propagation - lipid radical reacts with oxygen to form lipid peroxyl radical. This reacts further with an unsaturated lipid to form lipid peroxide.

47
Q

How does lipid peroxidation affect the bilayer?

A

Disrupts the hydrophobic environment of the bilayer and the lipid membrane integrity fails.

48
Q

What are endogenous sources of biological oxidants?

A

Electron transport chain
Peroxidase
Nitric oxide synthases
NADPH oxidases

49
Q

What are some exogenous biological oxidants?

A

Radiation
Pollutants
Drugs
Toxins

50
Q

What is the function of nitric oxide synthase?

A

A biological oxidant that forms nitric oxide for use as a signalling molecule in vasodilation, neurotransmission and S- nitrosylation. Nitric oxide is toxic at high levels

51
Q

How is nitric oxide formed?

A

Arginine is oxidised by nitric oxide synthase to citrulline and nitric oxide.

52
Q

What are the 3 types of nitric oxide synthase enzymes?

A
  1. Inducible nitric oxide synthase (iNOS) - immune response
  2. Endothelial nitric oxide synthase (eNOS) - signalling
  3. Neuronal nitric oxide synthase (nNOS) - signalling
53
Q

What 3 cellular defences protect against oxidative damage?

A
  1. Superoxide dismutase/catalase
  2. Glutathione
  3. Free radical scavengers
54
Q

What is the function of superoxide dismutase?

A

An enzyme that converts superoxide into hydrogen peroxide and oxygen. Stops superoxide initiating chain reactions such as lipid peroxidation.

55
Q

What is the function of catalase?

A

Converts hydrogen peroxide to water and oxygen. Protects cells against oxidative burst.

56
Q

What is glutathione?

A

A tripeptide that protects against oxidative damage (antioxidant).

57
Q

Describe how glutathione functions

A

Thiol group of the cysteine amino acid donates an electron to ROS. Glutathione reacts with another glutathione via disulphide bond, forming oxidised glutathione (GSSG). Enzyme glutathione peroxidase necessary for this reaction.

58
Q

What reaction does glutathione reductase catalyse?

A

Converts GSSG back to 2 x GSH. Catalysed the transfer from NADPH to the disulphide bond.

59
Q

Why is NADPH essential in reducing oxidative stress?

A

NADPH essential in reducing GSSG to regenerate glutathione. Glutathione is a cellular defence to ROS

60
Q

How does a G6PDH deficiency result in oxidative stress?

A

G6PDH enzyme is the rate limiting enzyme of the pentose phosphate pathway which produces NADPH. Without this pathway functioning efficiently, less NADPH will be produced and less glutathione will be able to be regenerated from GSSG

61
Q

Why is primaquine dangerous for individuals with G6PDH deficiency?

A

As primaquine (used to treat malaria) causes haemolysis and generates free radicals. As individuals with G6PDH deficiency are likely to have an impaired defence against oxidants, generating free radicals is likely to cause a significant increase in oxidative stress.

62
Q

What is the function of free radical scavengers?

A

To donate a hydrogen atom and its electron to free radicals in a non-enzymatic reaction.

63
Q

Name some free radical scavengers

A 
Vitamin E (lipid soluble antioxidant)
Vitamin C (water soluble antioxidant, regenerates reduced form of vitamin E)

(Carotenoids, uric acid, melatonin, flavonoids)

64
Q

What is respiratory burst?

A

An immune response to infection where there is rapid production and release of ROS (hydrogen peroxide and superoxide) from phagocytic cells (monocytes and neutrophils).

65
Q

What is the function of respiratory burst?

A

To destroy nearby bacterial or fungal cells, the phagocytic cells are also destroyed in the process.

66
Q

How is respiratory burst initiated?

A

Membrane bound enzyme complex NADPH oxidase transfers electrons from intrinsic NADPH to extracellular O2 to deliberately form superoxide radicals. The enzyme iNOS in phagocytic cells also produces nitric oxide which can go on to form peroxynitrite extracellularly by reacting with superoxide.

67
Q

What is chronic granulomatous disease?

A

Genetic defect in NADPH oxidase causing susceptibility to bacterial infections as oxidative burst cannot occur.

68
Q

What is galactosaemia?

A

When there is a deficiency in the enzymes required for galactose metabolism.

69
Q

What are the 3 enzymes that may be deficient in galactosaemia?

A

Galactokinase
UDP- galactose epimerise
Uridyl transferase

70
Q

Why are RBC with Heinz bodies more prone to haemolysis?

A

Heinz bodies bind to RBC membrane, altering rigidity and increasing mechanical stress when cells squeeze through capillaries.

71
Q

What clinical sign of G6PDH deficiency can be seen in a blood smear?

A

Heinz bodies/ blister cells

72
Q

Why does galactosaemia compromise cellular defences against oxidative damage?

A

Galactose metabolism cannot occur in the usual pathway due to enzyme deficiency (usually galactokinase) so instead is broken down by aldose reductase to produce galactilol. Increased activity of aldose reductase consumes excess NADPH. NADPH is no longer available to regenerate GSH from GSSG.

73
Q

Why do patients with galactosaemia develop cataracts?

A

Galactitol produced by aldose reductase accumulates in the lens of the eye, increasing osmotic pressure. Crystalline protein in the lens of the eye denatures, causing cataracts, clouding of the eye lens which may lead to blindness.

74
Q

What are symptoms for galactosaemia?

A 
Hepatomegaly 
Cirrhosis
Renal failure
Vomiting
Seizure + brain damage
Cataracts
Hypoglycaemia
75
Q

When consumed appropriately, how is paracetamol usually metabolised in the body?

A

Conjugated with glucoronide and sulphate in the liver.

76
Q

Why is consumption of 10g of paracetamol toxic?

A

Metabolism pathways of paracetamol become saturated. Metabolite NAPQI is produced which is extremely toxic to hepatocytes. NAPQI is a strong oxidising agent that reacts with GSH to form GSSG, depleting GSH levels in hepatocytes. NAPQI has a toxic effect on hepatic proteins causing them to covalently bond together. Toxic effects leads to destruction of liver cells ad liver failure which may result in death if left untreated.

77
Q

How is paracetamol overdoes treated?

A

Rapid treatment of n-acetylcysteine. Should be given within 8 hours, Replenishes glutathione, allowing the liver to metabolism NAPQI.

MEH (23 decks)

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