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Semester 2 MEH > L1: Oxidative Stress and Alcohol Metabolism > Flashcards

L1: Oxidative Stress and Alcohol Metabolism Flashcards

1
Q

What is the energy content of alcohol?

A

29 KJ/g

More energy than carbohydrates and protein.

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2
Q

Where is alcohol mainly metabolised? What happens to the remainder?

A

> 90% metabolised by the liver, the remainder is passively excreted in urine or on breath.

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3
Q

What are the main enzymes involved in alcohol metabolism?

A

Alcohol dehydrogenase and aldehyde dehydrogenase.

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4
Q

What is the role of alcohol dehydrogenase?

A

To oxidise alcohol to acetaldehyde..

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5
Q

What is the role of aldehyde dehydrogenase?

A

To oxidise acetaldehyde to acetate.

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6
Q

How can acetate be used?

A

It is converted to acetyl CoA (conjugates to Coenzyme A) which can then enter the TCA cycle or be used for fatty acid synthesis.

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7
Q

What is the minor pathway for alcohol metabolism?

A

Small amounts are oxidised by cytochrome P450 2E1 enzyme (CYP2E1) or catalysed by the brain.

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8
Q

What is the recommended alcohol limit for men and women? Over how many days?

A

14 units/week.

Spread over at least 3 days.

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9
Q

How quickly is alcohol metabolised? Why type of kinetic does it show?

A

One unit of alcohol is 8g. It is eliminated at a rate of 7g per hour. Roughly 1 unit per hour.
It follows zero order kinetics, meaning the rate of metabolism is constant.

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10
Q

What is the pathway for alcohol metabolism?

A

Add diagram slide 5.
Alcohol (ethanol) –> Acetaldehyde –> Acetate
1) Requires Alcohol Dehydrogenase and NAD+ –> NADH
2) Requires Aldehyde dehydrogenase and NAD+ –> NADH

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11
Q

What is responsible for the feeling of a hangover? What causes the dehydration?

A

Acetaldehyde.
It is a toxic metabolite.
Ethanol prevents the secretion of ADH leading to dehydration.

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12
Q

Define Km? Does aldehyde dehydrogenase have a high or low Km? Why?

A

The concentration of substrate which gives half the Vmax (maximum rate of reaction).
Low Km
Maintain low levels of acetaldehyde, toxic

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13
Q

What causes liver damage? What is a sign of liver damage?

A

Acetaldehyde.
Normally–> minimum by aldehyde dehydrogenase (low Km).
Acetaldhyde accumulation
Excess NADH and Acetyl- CoA changes in liver metabolism –>fatty liver, alcohol hepatitis and alcoholic cirrhosis.
Leaky liver plasma membrane –>transaminase and gamma glutamyl transpeptidase in the blood
Jaundice –> No up take or conjugation of bilirubin –> hyperbilirubinaemia.
Reduced protein synthesis –> decreased serum albumin –> oedema + decreased clotting factor–>increased blood clotting time.

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14
Q

What happens in excessive alcohol consumption?

A

Decrease in NAD+/NADH ratio and increase in acetyl-CoA.

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15
Q

What are the consequences of a decrease in NAD+/NADH ratio?

A

Inadequate NAD+…
1) for lactate –> pyruvate … lactate acidosis (blood), reduced exrection of uric acid (kidney- same transporter)–> urate crystals –> gout
(lactate+ NAD+ (+LDH) –> NADH + H+ + pyruvate)
2) for glycerol metabolism (+ pyruvate) –> deficit in gluconeogenesis –> hypoglycaemia
(glycerol (+ATP) –> Glycerol phosphate (+NAD+) –> DHAP –> Glycolysis
3) for fatty acid oxidation –> increased triacylglycerol synthesis –> fatty liver
(beta oxidation –> produces large amount of NADH so require NAD+)

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16
Q

What is the consequence of increased Acetyl-CoA with low NAD+/NADH ratio?

A

No NAD+ for TCA cycle
Increased fatty acid synthesis and ketone bodies –> triacylglycerides –> fatty liver (no beta oxidation due to decreased NAD+)
Lipoprotein –> removed FA but protein synthesis reduced due to excess alcohol–> therefore cannot be removed from the liver–> fatty liver

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17
Q

Name the drug commonly used for treatment of alcohol dependence? How does it work? What type of learning theory is this linked to?

A

Disulfiram.
Inhibits aldehyde dehydrogenase –> accumulation acetaldehyde –>symptoms of hangover.
Classical conditioning –> Pavlovian conditioning, Stimulus associated with outcome (bell associated with food, dogs started salivating when bell was rung even without the presence of food).

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18
Q

What do we mean by oxidative stress?

A

Imbalance between free radical and antioxidants in your body.

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19
Q

What are oxidants?

A

Free radicals, reactive oxygen species (ROS) and reactive nitrogen species (RNS).
Accept electrons

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20
Q

What diseases can oxidative stress lead to?

A 
Cellular damage caused by free radicals, ROS and RNS result in a wide range of diseases: 
Cardiovascular disease
Multiple sclerosis
Parkinson's disease
Pancreatitis
Cancer
Ischemia/ reperfusion injury
COPD
Crohn's disease
Rheumatoid Arthritis
Alzheimer's disease
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21
Q

What are free radicals?

A

An atom or molecule that contains one or more unpaired electrons and is capable of free independent (free) existence.

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22
Q

Why are free radicals bad?

A

They are usually very reactive and then to acquire electrons from other atoms, molecules or ions.
Reaction of one radical with a molecule typically generates a second radical thereby propagating damage.

23
Q

Why is oxygen not considered a free radical?

A

Oxygen is biradical, it has two unpaired electrons in different orbitals which means that it is stable.

24
Q

What are the different ROS and how are they formed?

A

Superoxide, Hydroxyl radical.
- O2 + e- –> superoxide (O2•-)
- Superoxiode + (2H+) + (e-) –> hydrogen peroxide
- (H2O2) (not a free radical but very reactive)
- H2O2 + (H+) + (e-) –> hydroxyl radical (OH•) + H20
- (OH•) + (H+) + (e-) –> H20
Diagram slide 13

25
Q

Which is the most damaging and reactive free radical?

A

Hydroxyl radical (OH•), reacts with anything.

26
Q

Give an example of an RNS? What does it combine with and produce?

A

Nitric oxide (NO•) and peroxynitrite (ONOO-)*

  • Nitric oxide (NO•) + Superoxide (O2-•) –> ONOO-
  • Peroxynitrite is not actually a free radical but is a powerful oxidant that can damage cells.
27
Q

How do ROS cause damage to DNA?

A

ROS can react with a base
- modify base leading to mispairing and mutation
ROS can react with a sugar
- can cause strand break and mutation upon repair

ROS reacts with DNA –> DNA damage –> failure in repair can lead to mutation –> can lead to cancer

28
Q

How can you measure the amount of oxidative damage?

A

You can measure the amount of 8-oxo-dG which gives you an idea about the amount of oxidative stress.

29
Q

What parts of a protein can the ROS interact with?

A

The protein backbone or the protein sidechain.

30
Q

What happens if ROS interacts with the protein backbone?

A

It results in fragmentation and then protein degradation.

31
Q

What happens if ROS interacts with the protein sidechain?

A

It can modify the amino acids, leading to change in protein structure which results in protein degradation, loss of function or gain of function.

32
Q

How can amino acids be modified?

A
  • Carbonyls
  • Hydroxylated adducts
  • Ring open species
  • Dimers (e.g. di-tyrosine)
  • Disulphine bond (cys)
33
Q

Why are disulphide bonds important? What do they form between? What happens if innappropiate disulphide bonds are formed?

A

Disulphide bonds play an important role in folding and stability of some proteins (usually secreted or in extracellular domains of protiens) e.g. human insulin
They from between the thiol groups of cystein residues.
Inappropriate disulphide bond formation occurs when ROS take electron from cysteines causing misfolding, crosslinking, and disruption of function.

34
Q

What happens during lipid peroxidation? Which disease does it play a role in?

A

Free radicals extract hydrogen atoms from polyunsaturated fatty acid in the membrane forming a lipid radical.
This interacts with oxygen to form a lipid peroxyl radical.
This causes a chain reaction –> neighbouring lipids get oxidated (lipid peroxidation) –> extensive damage in the membrane. Lipid bilayer is distrupted and membrane integrity fails.
Happens in atherosclerosis (hardening of the arteries).

35
Q

What are the two main sources of oxidants? Give a few examples from each category.

A

Endogenous and exogenous.
Endogenous: ETC, Nitric oxide synthase, NADPH oxidase, lippoxygenase, perioxidase (more on slide 18).
Exogenous: Radiation (X-rays, UV, cosmic), Pollutants, drugs (primaquine (anti-malarial)), Toxins (Paraquat (herbicide)).

36
Q

Describe how the ETC causes oxidative stress?

A

NADH and FADH2 supply e- to proton translocating complex in the ETC eventually they reduce oxygen to form H2O, occasionally the e- can escape from the ETC and react with dissolved O2 to form superoxide (O2-•) which then goes on to damage proteins and lipids.

37
Q

How does Nitric oxide synthase (NOS) cause oxidative stress? What are the different types of enzymes?

A

The enzyme NOS is a free radical which convert arginine to citrulline and the gasous substance NO•.
Inducible NOS (iNOS) –> produces high NO concentration in phagocytes for direct toxic effect.
Endothelial NOS (eNOS) and Neuronal NOS (nNOS) –> produce NO at much lower levels in a controlled fashion for signalling.
NO• at higher levels is toxic.

38
Q

What are the important functions of NO•?

A

NO• is an important signalling molecule causing vasodilation, neurotransmission and S-Nitrosulation.

39
Q

What happens during respiratory burst?

A

Part of microbial defence system
Phagocytic cells–> release superoxide and H2O2
ROS and peroxynitrite (ONOO-) destroy invading bacteria.

40
Q

How do white blood cells use ROS to kill bacteria/ pathogens?

A

White blood cells contain iNOS which combines with superoxide (O2-•) produced by NADPH oxidase to form peroxynitrite (ONOO-) which attacks the bacteria.
Superoxide can also produce H2O2 which can react with Cl- to produce hypochlorite (HOCl•) aka bleach, which kills bacteria.

41
Q

What defence systems do we have against ROS?

A
  • Superoxide dismutase and catalase deal with superoxide and H2O2 production.
  • Glutathione deals with H2O2
  • Free radical scavengers
42
Q

How does superoxide dismutase and catalase work?

A

Superoxide dismutase converts Superoxide to Hydrogen peroxide and oxygen.
Catalase converts hydrogen peroxide to water and oxygen.

43
Q

Why is superoxide dismutase so important? What are the isoenzymes?

A 
Primary defence as superoxide is a strong chain reaction initiator. 
3 isoeznymes 
- Cu+ Zn2+ cytosolic 
- Cu+ Zn2+ extracellular
- Mn2+ mitochondrial
44
Q

Why is catalase important?

A

Widespread enzyme, important to immune cells to prevent against oxidative burst.
Declining levels in hair follicles may explain grey hairs. (Bleaching from inside!)

45
Q

What is glutathione? How does it work?

A
  • Tripeptide of glycine, cysteine and glutamate- glutathione (GSH).
  • Cysteine contains a sulphydryl group which can donate an electron to a free radical (H2O2) mediated by glutathione peroxidase.
  • Cysteine then forms a disulphide bond with another glutathione molecule –> oxidised form glutathione disulphide (GSSG)
46
Q

How is GSSG reduced back to GSH?

A

Requires NADPH and glutathione reducatase.
Transfer of H atoms from NADPH to disulphide bond
Glutathione reductase requires selenium
This means the pentose phosphate pathway is therefore essential for protection against free radical damage.

47
Q

What is the pentose phosphate pathway? Why is it important? What is the rate limiting enzyme?

A

Pathway converts Glucose-6-phosphate to C5-sugar ribose when cell is in high energy state.
Important for production of NADPH which is needed for reducing power for biosynthesis, maintenance of GSH levels and detoxification reactions.
And produces C5-sugar ribose for nucleotide, DNA and RNA.
Rate limiting enzymes if glucose-6-phosphate dehydrogenase.

48
Q

How do free radical scavengers work? What important vitamins do this?
What are some of the others?

A 
Reduce free radical damage by donating hydrogen atoms and its electron to free radicals in nonenzymatic reactions. 
Vitamin E (lipid soluble antioxidant) prevents against lipid peroxidation reactions (lipid radicals) becomes oxidised Vitamin E. 
Vitamin C (water soluble antioxidant) important role in regenerating reduced form of Vitamin E.
Carotenoids, flavenoids, uric acid and melatonin.
49
Q

What is galactosaemia?

A

Ineffective galactose metabolism
Build up of galactitol –> problems such as cataracts, hypoglycemia, vomiting, seizures + brain damage, renal failure etc…

50
Q

What causes galactosaemia?

A

Deficiency in galactokinase, UDP-galactose 4’-epimerase or Uridyl transferase.
Galactose converted to galactitol by aldose reducatase.
Requires NADPH which compriomise ROS defences –> need to form reduced glutathione
Crystallin protein in lens of eye damaged –> cataracts.

51
Q

What happens during glucose-6-phosphate dehydrogenase deficiency? Why are RBC particularly susceptible?

A

First enzyme in the pentose phosphate pathway, –> limited amount of NADPH produced
NADPH required for reduction of oxidised glutathione (GSSG) to reduced glutathione (GSH).
Lower GSH means less protection against oxidative stress.
Oxidative stress: infection, drugs (antimalaria; Primoquine), broad beans etc…
Results in lipid peroxidation (cell membrane damage, lack of deformity leads to mechanical stress),
Protein damage leads to aggregates of cross-linked haemoglobin (Heinz bodies) –> Haemolysis.
RBC carry lots of O2 (converted to superoxide) and pentose phosphate pathway only source of NADPH defects in pathway limit amount of NADPH –> oxidative damage.

52
Q

What are Heinz bodies?

A

Precipitated haemoglobin.
Haemoglobin damaged by free radical–> proteins aggregate and stick to membrane–> increased mechanical stress as they squeeze through capillaries and recognised by spleen as damaged cells and removed, (can lead to anaemia).
Spleen tries to remove heinz bodies leading to blister cells (part of cell pinched off).

53
Q

How is paracetamol metabolised?

A

At prescribed levels safely metabolised by conjugation with glucaronide or sulphate in the liver.
At high levels paracetamol–> toxic metabolite NAPQI–> accumulates
NAPQI is an oxidant which can cause lipid peroxidation, damage to proteins and damage to DNA.
Cells try to reduce NAPQI levels by using up glutathione resulting in glutathione depletion and therefore susceptible to oxidative damage.

54
Q

What is used to treat paracetamol overdose?

A

Acetylcysteine.

Works by replenishing glutathione levels limiting the oxidative stress in the cells.

Semester 2 MEH (23 decks)

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