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2 MEH > 1 Alcohol Metabolism & Oxidative Stress > Flashcards

1 Alcohol Metabolism & Oxidative Stress Flashcards

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1
Q

Where does alcohol metabolism occur?

A
  • Liver >90%
  • Remainder is excreted passively in urine and on breath
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2
Q

What are the recommended limits for alcohol consumption?

A

14 units/week spread over at least 3 days for both men & women

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3
Q

Briefly describe the pathway involved in alcohol metabolism

A
  • 1) Alcohol–>Acetaldehyde
    • ​1) Alcohol dehydrogenase
  • 2)Acetaldehyde–>Acetate
    • 2) Aldehyde dehydrogenase
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4
Q

What happens when acetaldehyde accumulates?

A
  • Acetaldehyde is a toxic metabolite
  • Accumulation causes a “Hangover”
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5
Q

What happens to the acetate produced in alcohol metabolism?

A
  • Acetate is conjugated to coenzyme A to form acetyl-CoA
  • Acetyl-CoA:
  1. metabolised in TCA cycle
  2. utilised for fatty acid synthesis
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6
Q

How is acetaldehyde toxicity controlled?

A

Acetaldehyde toxicity normally kept to a minimum by aldehyde dehydrogenase (low Km for acetaldehyde)

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7
Q

How does liver damage occur?

A

Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde accumulation to cause liver damage

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8
Q

Identify three forms of liver damage resulting from prolonged and excessive alcohol consumption

A
  • “Fatty liver”
  • Alcoholic hepatitis
  • Alcoholic cirrhosis
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9
Q

Indicate how liver damage can lead to changes in liver metabolism

A
  • Excess NADH (decreased NAD:NADH)
  • Excess Acetyl-CoA
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10
Q

What are the systemic consequences of liver damage due to prolonged and excessive alcohol consumption? (3)

A
  • Lactic acidosis
  • Hypoglycaemia
  • Gout
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11
Q

Illustrate how excess NADH and Acetyl-CoA resulting from alcoholic liver damage can lead to the following consequences:

  • Lactic acidosis
  • Gout
  • Hypoglycaemia
  • Fatty liver
A
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12
Q

Which drug can be used to treat chronic alcohol dependence?

A

Disulfiram

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13
Q

What is oxidative stress?

A

Disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses

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14
Q

What is a free radical?

A

A free radical is an atom or molecule that contains 1/more unpaired electrons and is capable of independent existence e.g. OH•

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15
Q

Why are free radicals so damaging?

A
  • Free radicals are usually very reactive and tend to acquire electrons from other atoms, molecules or ions
  • Reaction of a radical with a molecule typically generates a second radical thereby propagating damage
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16
Q

What are the two types of free radicals found in the body?

A
  • Reactive Oxygen Species eg. Super oxide, Hydrogen peroxide
  • Reactive Nitrogen Species eg. Nitric oxide, Peroxynitrate
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17
Q

Which three structures can ROS damage?

A
  • DNA
  • Proteins
  • Lipids
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18
Q

Outline the two ways in which ROS can damage DNA

A
  • ROS reacts with base – mispairing
  • ROS reacts with sugar (ribose or deoxyribose) – strand break
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19
Q

What are the possible consequences of ROS damage to DNA?

A
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20
Q

Outline the two ways that ROS can damage proteins and the consequences of this.

A

If ROS takes electrons from cysteine- cause misfolding/crosslinking

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21
Q

Disulphide bonds are formed between thiol groups of cysteine residues and play an important role in folding and stability of some proteins.

What happens when ROS interfere with these bonds?

A

Inappropriate disulphide bond formation can occur if ROS takes electrons from cysteines causing misfolding, crosslinking and disruption of function e.g. enzyme

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22
Q

Which process in triggered when ROS react with lipids?

A

Lipid peroxidation

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23
Q

In three steps, describe how lipid peroxidation occurs

A

⇒ Free radical extracts H+ from a polyunsaturated fatty acid in membrane lipid

⇒ Lipid radical forms & reacts with O2 to form a lipid peroxyl radical

⇒ Chain reaction formed as lipid peroxyl radical extracts hydrogen from nearby fatty acid

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24
Q

What are the consequences of lipid peroxidation? (think membrane)

Study These Flashcards
A

Hydrophobic environment of bilayer disrupted and membrane integrity fails

25
Identify three endogenous sources of biological oxidants
- Electron transport chain (electrons accidently escape chain) - Nitric oxide synthases - NADPH oxidases
26
Identify four exogenous sources of biological oxidants
- Radiation- UV light, x-rays - Pollutants - Drugs (eg primaquine- anti-malarial) - Toxins (eg herbicide)
27
Explain how the ETC can be an endogenous source of ROS
- Electrons pass through ETC and reduce oxygen to form H2O at Complex IV - Occasionally electrons can accidently escape chain and react with dissolved O2 to form superoxide
28
Explain the pathway in which nitric oxide synthase acts as an endogenous source of ROS
Arginine → Citrulline + NO• ## Footnote - Nitric oxide synthase catalyses this reaction - NO• is toxic in high levels
29
What are the three types nitric oxide synthase?
- **iNOS:** inducible nitric oxide synthase (direct toxic effect in phagocytes) - **eNOS:** endothelial nitric oxide synthase (signalling) - **nNOS:** neuronal nitric oxide sytnthase (signalling)
30
Illustrate how biological oxidants are part of antimicrobial defence system
- Rapid release of superoxide & H2O2 from phagocytic cells - ROS and peroxynitrite destroy invading bacteria **=Respiratory Burst**
31
What is chronic granulomatous disease?
**Genetic defect** in **NADPH oxidase complex** Enhanced susceptibility to bacterial infections *e.g. pneumonia, cellulitis, impetigo, absesses*
32
Identify three cellular defences against biological oxidants
1. - Superoxide dismutase 2. - Catalase 3. - Glutathione
33
Explain the action of superoxide dismustase as a cellular defence
- Converts **superoxid**e to **hydrogen peroxide** and **oxygen** - **Primary defence** as superoxide is strong initiator of chain reactions
34
Explain the action of catalase as a cellular defence
- Converts hydrogen peroxide to water and oxygen - Important in **immune cells** to protect against **oxidative burst**
35
What is glutathione?
**Glutathione** is a **tripeptide synthesised** by body to protects against oxidative damage
36
Explain the action of glutathione as a cellular defence
1. ⇒ The thiol group of Cys **donates e− to ROS** 2. ⇒ GSH then reacts with another GSH to form a **disulphide (GSSG)** 3. --\> Glutathione reductase: 1. Reduces GSSG--\> GSH 2. Catalyses the transfer of electrons from NADPH to disulphide bond
37
Identify the two requirements necessary for the action of glutathione.
- Glutathione peroxidase requires **selenium** - NADPH from the **pentose phosphate pathway**
38
Which vitamins act as free radical scavengers?
- Vitamin C - Vitamin E
39
How do free radical scavengers act as cellular defences against biological oxidants?
Reduce free radical damage by **donating hydrogen atom** (and its electron) to free radicals in a nonenzymatic reaction
40
Explain and illustrate how Vitamin C and E act as free radical scavengers
- **Vitamin E:** lipid soluble antioxidant important for protection against lipid peroxidation - **Vitamin C:** water soluble antioxidant important in regenerating the reduced form of Vitamin E
41
Identify 5 symptoms of galactosaemia. (6)
- Hepatomegaly & cirrhosis - Renal failure - Vomiting - Seizure & brain damage - Cataracts - Hypoglycaemia
42
In galactosaemia, the accumulation of galactose can lead to the formation of cataracts. In four steps, describe how this occurs
1. ⇒ Increased activity of **aldose reductase** consumes excess NADPH 2. ⇒ Compromised defences against **ROS damage** 3. ⇒ **Crystallin protein** in lens of eye denatured (+ osmotic pressure) 4. ⇒ **Cataracts** form
43
In 5 steps, explain the consequences of GSPDH deficiency
⇒ Decreased G6PDH activity limits amount of **NADPH** ⇒ Less NADPH available for **reduction of GSSG** back to GSH ⇒ Lower GSH = less protection against **oxidative stress** ⇒ **Lipid** **peroxidation** & **protein** **damage** ⇒ **Haemolysis**
44
What are heinz bodies?
- **Heinz bodies** are aggregates of cross-linked haemoglobin - The precipitated haemoglobin _stains dark_ within _RBCs_
45
What are the effects of heinz bodies?
- Bind to cell membrane **altering rigidity** - **Increased mechanical stress** when cells squeeze through small capillaries - Spleen removes bound Heinz bodies resulting in **“blister cells”**
46
How much energy does alcohol contain?
29kJ/g

>protein

>carbohydrates
47
What conditions can be cause by prolonged and excessive alcohol consumption and why? (3)
1. 'Fatty liver' 2. Alcohol hepatitis 3. Alcohol Cirrhosis (scar tissue formation) *Due to increase levels:* * *NADH* * *Acetyl-CoA*
48
How can chronic alchohol consumption cause gout?
* Lactate accumulates in blood * Kidney's inability to excrete uric acid **reduced** * **Urate crystals** accumulate in tissues=gout
49
How can chronic alcohol consumption cause hypoglycaemia?
* Inadequate NAD+ for glycerol metabolism * Inadequate NAD+ for conversion of lactate--\>pyruvate * Gluconeogenesis deficit
50
How can chronic alcohol consumption cause a 'fatty liver'?
* Decrease NAD+/NADH ratio * Inadequate NAD+ for fatty acid oxidation * Increased acetyl-CoA- increased synthesis of fatty acids and ketone bodies- increased Triacylglycerol synthesis
51
What is disulfiram used to treat and how does it work?
**Chronic Alcohol dependence** Inhibits aldehyde dehydrogenase Acetaldehyde accumulates- symptoms of hangover
52
Name some diseases which can be caused by oxidative stress.
1. Cancer 2. MS 3. CVS disease 4. Rheumatoid arthiritis 5. Crohn's disease 6. COPD 7. Alzheimer's
53
What is Nitric Oxide used for in the body?
Signalling (Vasoldilation, neurotransmission)
54
What is galactosaemia?
Deficiency in any 3 enzymes favouring conversion of galactose--\> galactitol
55
What are heinz bodies a clinical sign of?
G6PDH deficiency
56
What are the symptoms of a G6PDH deficiency?
1. Anaemia 1. HB conc decreased 2. Increased reticulocytes 2. Jaundice 1. By-product of RBC breakdown
57
How is Paracetamol safely metabolised (usually)?
Conjugation with: - glucuronide - sulphate
58
What happens (metabolically) in a paracetamol overdose?
NAPQI toxis metbolite- accumulates: * Oxidative damage- liver cell * Glutathione depletion
59
What antidote is used for a paracetamol overdose and how does it work?
**Acetylcysteine**- replenish Glutathione levels

2 MEH (18 decks)

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