L1: Alchohol Metabolism & Oxidative Stress Flashcards

(62 cards)

1
Q

Put the following in order of highest energy content:

  • Fat
  • Protein
  • Carbohydrate
  • Alcohol
A
  1. ) Fat
  2. ) Alcohol
  3. ) Protein
  4. ) Carbohydrate

(Carbs & proteins same)

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2
Q

Where is most of alcohol metabolised? How is the remainder excreted?

A

90% metabolised by the liver.

Remainder excreted passively in urine and on breath

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3
Q

Describe the process of alcohol metabolism in the liver, include:

  • enzymes
  • products used/generated by reaction
A
  1. ) Alcohol oxidised by alcohol dehydrogenase to acetaldehyde (NAD+ to NADH)
  2. ) Acetaldehyde oxidised to acetate by aldehyde dehydrogenase (NAD+ to NADH)
  3. ) Acetate converted to acetyl~CoA and used in:
    - TCA cycle
    - fatty acid synthesis
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4
Q

How are smaller amounts of alcohol metabolised?

A
  • Oxidised by cytochrome P450 2E1 enzyme (CYP2E1) in liver

- Catalase in brain

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5
Q

What’s recommended unit intake of alcohol?

A

14 units/week spread over 3 days for BOTH MEN AND WOMEN.

One unit= 8g of alcohol or 2ml of pure ethanol

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6
Q

What’s the elimination rate of alcohol?

A

7g per hour (CONSTANT)

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7
Q

What causes a hangover?

A

Accumulation of acetaldehyde (a toxic metabolite)

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8
Q

How does acetate form acetyl~CoA?

A

Acetate conjugated with coenzyme A to form Acetyl~CoA

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9
Q

How is acetaldehyde toxicity normally kept to a minimum?

A
  • Aldehyde dehydrogenase metabolises it into acetate as soon as it is formed
  • Enzyme also has a low Km for acetaldehyde therefore
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10
Q

Prolonged and excessive alcohol consumption can cause liver damage due to a build up of what metabolite?

A

Acetaldehyde

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11
Q

Excess NADH and Acetyl~CoA can lead to…?

A

Changes in liver metabolism

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12
Q

A decrease in NAD+/NADH ratio results in [NAD+] being inadequate for what three things?

A
  • Fatty acid oxidation
  • Conversion lactate to pyruvate
  • Metabolism of glycerol
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13
Q

A decrease in NAD+/NADH ration results in insufficient NAD+ for conversion of lactate to pyruvate; state two problems associated with a build up of lactate.

A
  1. ) Lactic acidosis- decreased utilisation of lactate in liver leads to accumulation of lactate in blood
  2. ) Decreases kidneys ability to excrete uric acid- can exacerbate gout
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14
Q

What is gout?

A

Inflammatory condition resulting from defective purine metabolism leading to increased production of uric acid. Also exacerbated by accumulation of lactate in blood as this decreases kidneys ability to excrete uric acid.

Uric acid is by-product of purine metabolism and as it’s levels in blood increase it forms monosodium crystals which accumulate in joint tissues causing pain and swelling.

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15
Q

What causes fatty liver?

A

There’s an increased availability in acetyl~CoA but it cannot be oxidised as there’s low NAD+/NADH ratio resulting in increased synthesis of fatty acids and ketones. Fatty acids are converted into triacylglycerols; these cannot be transported out of liver cells because of lack of lipoprotein synthesis- causing fatty liver.

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16
Q

Changes in liver metabolism can cause three diseases of liver; state these.

A
  • Fatty liver
  • Alcoholic hepatitis
  • Alcoholic cirrhosis (scar tissue in liver)
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17
Q

Describe how chronic alcohol consumption can lead to hypoglycaemia?

A

Decrease in NAD+/NADH ratio; therefore, inadequate NAD+ for glycerol metabolism leading to deficit in gluconeogenesis which can cause hypoglycaemia.

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18
Q

How does disulfiram work as a treatment for chronic alcohol dependence?

A

Inhibits aldehyde dehydrogenase. When a patient drinks, acetaldehyde will accumulate causing symptoms of a hangover and therefore ‘putting the patient off’ having an alcoholic drink

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19
Q

Define oxidative stress.

A

Imbalance of free radicals/oxidants (e.g. ROS, RNS) and body’s defence mechanisms against free radicals.

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20
Q

What’s a free radical?

A

Atom or molecule that contains one or more unpaired electrons and is capable of independent existence

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21
Q

Are radicals reactive?

A

Free radicals usually very reactive- acquire electrons from other atoms, molecules or ions. Reaction of a radical with a molecule typically generates a second radical thereby propagating the damage

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22
Q

State three reactive oxygen species (ROS’s) and two reactive nitrogen species (RNS’s).

A
ROS= superoxide radical (O2 -) & hydroxyl radical & hydrogen peroxide
RNS= nitric oxide radical (NO) & peroxynitrite (ONOO-)
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23
Q

How is superoxide formed?

A

Adding electron to molecular oxygen

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24
Q

How is hydroxyl radical formed?

A

Addition of H+ and e- to hydrogen peroxide (forms hydroxyl radical and water)

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25
How is peroxynitrite formed?
Nitric oxide radical and superoxide radical react
26
Are hydrogen peroxide and peroxynitrite free radicals?
No but.... - Hydrogen peroxide can react to from free radicals e.g. with Fe2+ - Peroxynitrite is powerful oxidant
27
State the two ways ROS can damage DNA.
- ROS reacts with base: lead to mispairing or mutation - ROS reacts with sugar: cause strand breakage or mutation on repair Failure to repair damage can lead to cancer
28
What can be used as a measure of the oxidative damage to DNA caused by ROS?
8-oxo-dG
29
ROS can cause damage to proteins; state what happens if damage is caused to: a. ) Backbone b. ) Sidechain
a. ) Backbone: fragmentation -> protein degradation b. ) Sidechain: modified amino acid -> change in protein structure -> protein degration or loss of function or gain of function
30
How can ROS cause inappropriate disulphide bonds?
ROS removes electrons from thiol group in cysteines causing disulphide bond formation leading to misfolding, crosslinking and disruption of function.
31
How can ROS cause inappropriate disulphide bonds?
ROS removes electrons from thiol group in cysteines causing disulphide bond formation leading to misfolding, crosslinking and disruption of function. (2 H+, 2 e- removed when one disulphide bond formed as one from each thiol group)
32
Describe how ROS can damage lipids.
- Free radical extracts H atom from polyunsaturated fatty acid - Lipid radical formed - Lipid radical react with oxygen to form lipid peroxyl radical - Lipid peroxyl radical reacts with nearby fatty acid and extracts H atom forming lipid peroxide and causing the nearby fatty acid to become a radical- CHAIN REACTION
33
What happens to membrane if ROD damage lipid membranes?
Hydrophobic environment of bilayer disrupted and membrane integrity fails
34
State some endogenous sources of biological oxidants
- Electron transport chain - Nitric oxide synthases - NADPH oxidases
35
State some exogenous sources of biological oxidants
- Radiation (UV, x-rays, cosmic rays) - Drugs (e.g. primaquine- antimalarial) - Toxins (e.g. paraquat- herbicide) - Pollutants
36
Explain how the electron transport chain is a source of ROS
NADH and FADH2 supply electrons from metabolic substrates; electrons pass through ETC and reduce oxygen to form water at complex IV. Occasionally electrons can accidently escape chain and react with dissolved O2 forming superoxide.
37
Explain how nitric oxide synthase is a source of ROS
Nitric oxide synthase converts: Arginine -> citrulline + nitric oxide radical (NADPH + O2) used, (NADP+ + H20) formed
38
As well as being a free radical that is toxic at high levels, nitric oxide radical is also a signalling molecule for what three things?
- Vasodilation - Neurotransmission - S-Nitrosylation
39
State the three types of nitric oxide synthase (NOS) and where they are found.
iNOS (inducible nitric oxide synthase): produces high [NO] in phagocytes for direct toxic effect eNOS (endothelial nitric oxide synthase): signalling nNOS (neuronal nitric oxide synthase): signalling
40
Describe what happens during respiratory burst and the aim.
Rapid release of superoxide and hydrogen peroxide from phagocytic cells. ROS and peoxynitrite destroy invading bacteria as part of antimicrobial defence system.
41
What is chronic granulomatous disease?
Genetic defect in NADPH oxidase complex (see image page 22 lecture) in phagocytic cells; results in increased susceptibility to bacterial infections.
42
What does the enzyme superoxide dismutase do/what is it's role?
Superoxide dismutase (SOD) converts: Superoxide -> hydrogen peroxide + oxygen (2H+ in, 02 out) It is primary defence as it is a strong initiator of chain reactions.
43
What does the enzyme catalase do/what is it's role?
Catalase converts: Hydrogen peroxide -> 2Water + Oxygen It is important in immune cells as protects against oxidative burst.
44
What is a suspected reason for grey hair as you age?
Declining levels of catalase in hair follicles therefore increase in hydrogen peroxide (bleach).
45
Hydrogen peroxide is toxic therefore it requires two enzymes to maintain it's concentration- state the enzymes.
Superoxide dismutase and catalase.
46
What is glutathione?
Glutathione is a tripeptide synthesised by body to protect against oxidative damage. (Glycine, Cysteine and Glutamate amino acids)
47
How does glutathione protect against oxidative damage?
- Thiol group of Cys donates electron to ROS - Enzyme glutathione peroxidase reacts GSH with another GSH to from disulphide (GSSG) {hydrogen peroxide to water reaction occurs alongside)
48
What does glutathione peroxidase require?
Selenium
49
How is GSSG converted back to GSH?
GSSG reduced back to GSH by glutathione reductase which catalyses transfer of electrons from NADPH to disulphide bond
50
Why is pentose phosphate pathway essential for protection against free radical damage?
It produces NADPH which is required by glutathione reductase as source of electrons for reduction of disulphide bond in order to convert GSSG (oxidized/non-protective form) to GSH (reduced/protective form)
51
What's the rate limiting enzymes in pentose phosphate pathway?
Glucose-6-phosphate dehydrogenase
52
How do free radical scavengers protect against ROS? State some examples.
Reduce free radical damage by donating hydrogen atom (and it's electron) to free radicals in non-enzymatic reactions. Vitamin E, vitamin C, uric acid, melatonin
53
Explain why both vitamin E and C are important free radical scavengers.
Vitamin E= lipid soluble therefore important for protection against lipid peroxidation Vitamin C= water soluble. Important role in regenerating reduced (protective) form of vitamin E
54
Explain how galactosaemia can lead to cataracts.
Deficiency in any of three enzymes (galactokinase, uridyl transferase and UDP-galactose epimerase) leads to build up of galactose and therefore increased conversion of galactose to galactitol by enzyme aldose reductase- this uses NADPH. Depletes NADPH levels, less protection against ROS damage hence crystalline protein in lens of eyes denatured.
55
State some symptoms of galactosaemia.
- Cataracts - Vomiting - Renal failure - Hypoglycaemia - Seizure and brain damage
56
Explain the consequences of glucose-6-phosphate dehydrogenase deficiency.
- Decreased NADPH levels - NADPH required for reduction of oxidised form of glutathione (GSSG) to reduced form (GSH) - Lower GSH therefore less protection against oxidative stress - Less GSSG converted back to GSH, then less GSH oxidised to GSSG; as a result, less hydrogen peroxide converted to water (as glutathione peroxidase converts hydrogen peroxide to water) - Hydrogen peroxide= toxic. Can cause Heinz bodies
57
What are Heinz bodies and how are they formed?
Clumps of denatured haemoglobin/precipitated haemoglobin which bind to cell membrane and alter rigidity causing increased mechanical stress when RBCs move through capillaries. Stain dark.
58
How are Heinz bodies removed?
Spleen- results in blister cells.
59
The presence of Heinz bodies is a sign of what deficiency?
Glucose-6-phophate dehydrogenase
60
At prescribed dosage how is paracetamol metabolised?
By conjugation with glucuronide or sulphate.
61
What happens when high levels of paracetamol are ingested?
Toxic metabolite NAPQI accumulates which has direct toxic effects as it is an oxidant (lipid peroxidation, damage to proteins, damage to DNA)
62
How do you treat high levels of NAPQI due to paracetamol overdose?
Acetylcysteine- it stimulates cells to produce glutathione levels as it has been used up trying to protect against oxidative damage by toxic NAPQI