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1
Q

Where is the majority of alcohol metabolised?

A

The liver (over 90%)

2
Q

Name the 3 steps by which alcohol is converted to acetyl-CoA

A
  1. Alcohol to acetaldehyde (by alcohol dehydrogenase)
  2. Acetaldehyde to acetate (by aldehyde dehydrogenase
  3. Acetate (conjugated to CoA) to form Acetyl-CoA - can be used in TCA cycle or for fatty acid synthesis
3
Q

What is the recommended alcohol limit for men and women per week?

A

14 units a week - spread over at least 3 days

4
Q

What is 1 unit of alcohol in grams?

A

8g

5
Q

What redox reaction takes place alongside enzymatic activity of alcohol dehydrogenase and aldehyde dehydrogenase?

A

NAD+ to NADH (at each step)

6
Q

What metabolism when accumulated causes a hangover?

A

Acetaldehyde (it is a toxic metabolite)

7
Q

How is acetaldehyde normally kept to a low level?

A

Because aldehyde hydrogenase has a low kM for acetaldehyde

8
Q

Alcohol oxidation results in conversion of NAD+ to NADH. What 3 effects does lack of NAD+ have?

A
  1. Not enough NAD+ for conversion of lactate to pyruvate
  2. Not enough NAD+ for glycerol metabolism
  3. Not enough NAD+ for fatty acid oxidation
9
Q

What happens when there is an increase in Acetyl-CoA?

A

There is increased synthesis of fatty acids and ketone bodies

10
Q

Disulfiram can be used in treatment of alcohol dependence. Explain how it works

A

It is an inhibitor of aldehyde dehydrogenase

Acetaldehyde accumulates giving the person the symptoms of a hangover

11
Q

What is used in the treatment of alcohol dependence?

A

Disulfiram

12
Q

What is a free radical?

A

An atom or molecule that contains one or more unpaired electrons
They are very reactive and can cause damage to cells

13
Q

Most reactive oxygen species are free radicals. What other type of molecules cause damage?

A

Reactive nitrogen species

14
Q

Oxygen is a biradical. What does this mean?

A

It has 2 unpaired electrons but in different orbitals

15
Q

What is produced by adding an electron to oxygen?

A

Superoxide

16
Q

What is produced when 2 hydrogen atoms and an electron are added to superoxide?
Is this a free radical?

A

Hydrogen peroxide

No it is not a free radical but it can react with iron to produce free radicals

17
Q

What is the most damaging free radical?

A

Hydroxyl radical

18
Q

What does superoxide react with to produce peroxynitrite?

A

Nitric oxide

19
Q

When nitric oxide reacts with superoxide what does it form?

A

Peroxynitrite

20
Q

What are the 2 types of damage reactive oxygen species can cause to DNA?

A
  1. ROS reacting with the base = can lead to mispairing and mutation
  2. ROS reacting with the sugar = can cause strand break and mutation on repair
21
Q

What can be used as a measure of the amount of oxidative damage?

A

The amount of 8-oxo-dG present in cells

22
Q

What 2 parts of the protein can reactive oxidative species damage?

A

The backbone

The sidechain

23
Q

What can happen if ROS damages the side chain of a protein?

A

Lots of chemical modifications can occur such as disulphide bonds can form
This can lead to gain or loss of function

24
Q

Because which groups are disulphide bonds in proteins usually formed?

A

Thiol groups

25
Q

What happens when ROS damage to lipids takes place?

A

It starts a chain reaction
A lipid radical is formed which can react with oxygen to form a lipid peroxyl radical
Lipid peroxyl radical extracts hydrogen from a nearby fatty acid and sets of a chain reaction within the lipid bilayer

26
Q

Give 4 examples of exogenous source of ROS/RNS

A
  1. Toxins
  2. Drugs eg antimalarial drug
  3. Radiation eg x-rays
  4. Pollutants
27
Q

Give 3 examples of endogenous source of ROS/RNS

A
  1. Electron transport chain
  2. Nitric oxide synthases
  3. NADPH oxidases
28
Q

How can ROS be formed during the electron transport chain?

A

Normally, electrons in ETC reduce oxygen to form H20

Sometimes electrons can escape and react with oxygen to form superoxide

29
Q

There are 3 types of nitric oxide synthase. 2 are used in signalling and 1 in used by phagocytes to produce toxic effects. What are they?

A
  1. Inducible NO synthase (used by neutrophils in particular to kill bacteria)
  2. Endothelial NO synthase
  3. Neuronal NO synthase
30
Q

What is respiratory burst?

A

The rapid release of superoxide and hydrogen peroxide from phagocytic cells to destroy bacteria

31
Q

What do superoxide and NO form?

A

Peroxynitrite radicals

32
Q

What are released from secretory granules within phagocytes?

A

Myeloperoxidase

33
Q

How is superoxide formed by the phagocytes?

A

NADPH oxidase oxidises NADPH and oxygen to form superoxide

34
Q

What role does superoxide dismutase have?

What is it’s role in cellular defence?

A

SOD - superoxide dismutase converts superoxide to hydrogen peroxide and oxygen
It is involved in cellular defence because superoxide can initiate chain reactions

35
Q

What role does catalase have in cellular defence?

What happens if you have reduced catalase?

A

It converts hydrogen peroxide to oxygen and water

Reduced catalase = why hair follicles turn grey (increased levels of hydrogen peroxide)

36
Q

How does glutathione play a role in cellular defense?

A

Glutathione = tripeptide
One residue = cysteine
The thiol group of cysteine donates its election to a ROS
Cysteine then forms a bond with another cysteine residue (forming a disulphide bond)

37
Q

What is disulphide? How is it formed?

A

It is the oxidised form of glutathione (2 cysteine residues come together forming a disulphide bond)

38
Q

What enzyme removes an electron from the thiol group on cysteine?
What does this enzyme require?

A

Glutathione peroxidase

It requires selenium

39
Q

How is disulphide reduced back to glutathione?

A

By glutathione reductase

It uses the electron from NADPH to do this

40
Q

Why is the pentose phosphate pathway essential for cellular damage?

A

Because the NADPH from the pentose phosphate pathway is required to provide the electron for reducing GSSG back to GSH (Glutathione)

41
Q

What do free radical scavengers do?

Give 2 examples

A

They reduce free radical damage by donating a hydrogen atom and its electron to free radicals in a non-enzymatic reaction
Examples: Vitamin E and Vitamin B

42
Q

What is oxidative stress?

A

An imbalance of oxidants vs cell defense

43
Q

Deficiency in which 3 enzymes can result in galactosaemia?

A
  1. Uridyl transferase
  2. Galactokinase
  3. UDP-galactose epimerase
44
Q

Explain how build up of galactose can lead to cataracts

A
  • increase in galactose increases activity of aldose reductase which converts galactose to galactitol
  • aldose reductase uses NADPH in the reaction
  • NADPH is required for cellular defense (in the reduction of oxidised glutathione to glutathione)
  • when this is used up there is an increased risk of damage by ROS (as glutathione levels decreased)
  • damage can occur to proteins especially proteins in lens of eye (crystallin) which leads to cataracts
45
Q

How can a G6PDH deficiency lead to oxidative stress?

A

Glucose-6-phosphate dehydrogenase is needed to convert glucose 6P to 6-phosphogluconate. At the same time NADP is reduced to NADPH.
If G6PDH is deficient there will not be enough NADPH needed to supply the electron for reduction of oxidised glutathione to glutathione

46
Q

What are heinz bodies?

What are they a sign of?

A

They are clumps of damaged haemoglobin within the RBC

They are a sign of G6PDH deficiency

47
Q

At prescribed dosage what is paracetamol normally metabolised by?

A

Glucuronide or sulphate

48
Q

With happens when high levels of paracetamol accumulates?

A

NAPQI is produced and accumulates which can have direct toxic effects on the liver

49
Q

What does the liver do to try and combat accumulation of NAPQI?

A

It reacts NAPQI with glutathione

50
Q

Reaction of glutathione with NAPQI can lead to glutathione depletion (and increased risk of oxidative stress). How can you combat this?

A

Giving the patient acetylcysteine treatment = it works by replenishing glutathione levels

51
Q

Name 3 major nitrogen containing compounds and 1 smaller key nitrogen containing compound

A
  1. Amino acids
  2. Proteins
  3. Purines and pyrimidines
  4. Creatine
52
Q

What is creatinine?

A

It is the breakdown product of creatine and creatine phosphate in muscle

53
Q

What is creatinine a marker of?

Explain how it is excreted

A

Marker of renal function - it is raised when nephrons are damaged
Creatinine is filtered via kidneys into urine
The amount of creatinine excreted is proportional to muscle mass

54
Q

When might you expect to see a positive nitrogen balance?

A

When the intake of nitrogen is greater than output such as when a person is pregnant or growing

55
Q

What happens to dietary proteins when digested?

A

They are broken down to free AAs and stored in the “AA pool”
Some are used to make proteins used for hair skin and nails
Some are used to synthesise nitrogen containing compounds

56
Q

In the liver what are AAs broken

down into it needed for energy?

A

Carbon skeleton and amine group
Carbon skeleton is broken down into either ketogenic AAs or glucogenic AAs depending on side chain
Amine group is broken down into urea and excreted in urine

57
Q

Give an example of a glucogenic AA and a ketogenic AA

What are they converted into?

A
Glucogenic:
Alanine 
Glycine
Cysteine 
Serine
Ketogenic:
Lysine 
Leucine

Glucogenic AAs go through gluconeogenesis to produce glucose
Ketogenic AAs are converted to ketone bodies to produce energy

58
Q

What are the 3 largest stores of fuel?

A
  1. Triacylglycerol
  2. Glycogen
  3. Muscle protein
59
Q

What are the 2 main pathways that remove nitrogen from AAs?

A
  1. Transamination

2. Deamination

60
Q

What happens to the amino group of AAs?

What do most of them get funnelled to?

A

They can be funnelled to either glutamate or aspartate to produce
Most are funnelled to glutamate via alpha ketoglutarate

61
Q

What 2 aminotransferase enzymes are measured in liver function tests and what do they do?

A
  1. Alanine aminotransferase (ALT) - converts alanine to glutamate
  2. Aspartate aminotransferase (AST) - converts glutamate to aspartate
62
Q

What can death cap mushrooms cause?

A

Acute liver failure as plasma ALT (plasma alanine transferase) levels are 20 times the normal levels

63
Q

What happens in transamination?

A

The amine group of 1 AA is swapped for an oxygen in a keto acid to produce a different AA and a different keto acid

64
Q

What happens in deamination?

A

The amino group from an AA is liberated and becomes a free ammonia (toxic)
It is converted to urea or excreted directly in urine

65
Q

What are the input and output of the urea cycle?

A
Input= glutamate and aspartate 
Output = urea excreted in the urine
66
Q

Where does the urea cycle occur and how many enzymes are involved?

A

In the liver

5 enzymes are involved

67
Q

How is ammonia removed from tissues?

A
  1. Combination of ammonia and glutamate to form glutamine which can be transported to kidney or liver
  2. Combination of ammonia and pyruvate to form alanine which can be transported to liver
68
Q

What are the 2 inborn errors of amino acid metabolism?

A

PKU

Homocystinuria

69
Q

What is PKU?

A

Most common inborn error of AA metabolism
Deficiency in phenylalanine hydroxylase so accumulation of phenylalanine in tissue plasma and urine and phenylketones in urine

70
Q

What happens if there is a deficiency in phenylalanine hydroxylase?
What is this condition called?

A

If there is a deficiency in this phenylalanine cannot be converted to tyrosine which is needed to produce catacholamines and thyroid hormones for example
Condition = PKU

71
Q

What is homocystinurias?

A
Problem breaking down methionine (often from defect in cyststhionine b-synthase)
Excess homocystine (oxidised homocysteine) which affects CT, muscles, CNS, CVS