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MEH unit > S3) Alcohol Metabolism & Oxidative Stress > Flashcards

S3) Alcohol Metabolism & Oxidative Stress Flashcards

1
Q

Where does alcohol metabolism occur?

A
  • >90% alcohol is metabolised by liver
  • 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
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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 is metabolised in TCA cycle / 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 consequences of liver damage due to prolonged and excessive alcohol consumption?

A
  • Lactic acidosis
  • Fatty liver
  • 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

Explain how Disulfiram treats chronic alcohol dependence

A
  • Disulfiram is an inhibitor of aldehyde dehydrogenase
  • If patient drinks alcohol acetaldehyde will accumulate causing symptoms of a ‘hangover’
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14
Q

Cellular damage caused by ROS & RNS is a significant component in a wide range of disease states.

Identify some

A
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15
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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16
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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17
Q

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

A
  • Reactive Oxygen Species
  • Reactive Nitrogen Species
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18
Q

Describe the pathway involved in the formation of reactive oxygen species

A
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19
Q

Explain how reactive nitrogen species are formed

A

O2•- + NO• → ONOO-

  • Superoxide can react with nitric oxide to produce peroxynitrite
  • Peroxynitrite is not a free radical, but is a powerful oxidant which damages cells
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20
Q

Which three structures can ROS damage?

A
  • DNA
  • Proteins
  • Lipids
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21
Q

Outline the two ways in which ROS can damage DNA

A
  • ROS reacts with base – modified base can lead to mispairing and mutation
  • ROS reacts with sugar (ribose or deoxyribose) – causing strand break and mutation
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22
Q

What are the possible consequences of ROS damage to DNA?

A
23
Q

Outline, in detail, the two ways that ROS can damage proteins and the consequences of this

A
24
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

25
Q

Which process in triggered when ROS react with lipids?

A

Lipid peroxidation

26
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

27
Q

What are the consequences of lipid peroxidation?

A

Hydrophobic environment of bilayer disrupted and membrane integrity fails

28
Q

Identify three endogenous sources of biological oxidants

A
  • Electron transport chain
  • Nitric oxide synthases
  • NADPH oxidases
29
Q

Identify four exogenous sources of biological oxidants

A
  • Radiation
  • Pollutants
  • Drugs
  • Toxins
30
Q

Explain how the ETC can be an endogenous source of ROS

A
  • 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
31
Q

Explain the pathway in which nitric oxide synthase acts as an endogenous source of ROS

A

Arginine → Citrulline + NO•

  • Nitric oxide synthase catalyses this reaction
  • NO• is toxic in high levels
32
Q

What are the three types nitric oxide synthase?

A
  • iNOS: inducible nitric oxide synthase (direct toxic effect in phagocytes)
  • eNOS: endothelial nitric oxide synthase (signalling)
  • nNOS: neuronal nitric oxide sytnthase (signalling)
33
Q

Illustrate how biological oxidants are part of antimicrobial defence system

A
  • Rapid release of superoxide & H2O2 from phagocytic cells
  • ROS and peroxynitrite destroy invading bacteria
34
Q

What is chronic granulomatous disease?

A

Chronic granulomatous disease is a condition caused by a genetic defect in NADPH oxidase complex leading to an enhanced susceptibility to bacterial infections e.g. pneumonia, cellulitis, impetigo

35
Q

Identify three cellular defences against biological oxidants

A
  • Superoxide dismutase
  • Catalase
  • Glutathione
36
Q

Explain the action of superoxide dismustase as a cellular defence

A
  • Converts superoxide to hydrogen peroxide and oxygen
  • Primary defence as superoxide is strong initiator of chain reactions
37
Q

Explain the action of catalase as a cellular defence

A
  • Converts hydrogen peroxide to water and oxygen
  • Important in immune cells to protect against oxidative burst
38
Q

What is glutathione?

A

Glutathione is a tripeptide synthesised by body to protects against oxidative damage

39
Q

Explain the action of glutathione as a cellular defence

A

⇒ The thiol group of Cys donates e− to ROS

⇒ GSH then reacts with another GSH to form a disulphide (GSSG)

⇒ GSSG is reduced back to GSH by glutathione reductase which catalyses the transfer of electrons from NADPH to disulphide bond

40
Q

Identify the two requirements necessary for the action of glutathione

A
  • Glutathione peroxidase requires selenium
  • NADPH comes from the pentose phosphate pathway
41
Q

Which vitamins act as free radical scavengers?

A
  • Vitamin C
  • Vitamin E
42
Q

How do free radical scavengers act as cellular defences against biological oxidants?

A

Free radical scavengers reduce free radical damage by donating hydrogen atom (and its electron) to free radicals in a nonenzymatic reaction

43
Q

Explain and illustrate how Vitamin C and E act as free radical scavengers

A
  • 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
44
Q

Identify 5 symptoms of galactosaemia

A
  • Hepatomegaly & cirrhosis
  • Renal failure
  • Vomiting
  • Seizure & brain damage
  • Cataracts
45
Q

In galactosaemia, the accumulation of galactose can lead to the formation of cataracts.

In four steps, describe how this occurs

A

⇒ Increased activity of aldose reductase consumes excess NADPH

⇒ Compromised defences against ROS damage

⇒ Crystallin protein in lens of eye denatured (+ osmotic pressure)

⇒ Cataracts form

46
Q

In 5 steps, explain the consequences of GSPDH deficiency

A

⇒ 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

47
Q

What are heinz bodies?

A
  • Heinz bodies are aggregates of cross-linked haemoglobin
  • The precipitated haemoglobin stains dark within RBCs
48
Q

What are the effects of heinz bodies?

A
  • Bind to cell membrane altering rigidity
  • Increased mechanical stress when cells squeeze through small capillaries
  • Spleen removes bound Heinz bodies resulting in “blister cells”
49
Q

Describe paracetamol metabolism in terms of the following:

  • Normal conjugation
  • Toxic accumulations
  • Treatment
  • Oxidative damage
A
50
Q

why do red blood cells cintain lots of NADPH

A

NADPH reduces oxidative stress

51
Q

role of NADPH in heinz bodies, jaundice and anemia

A
  • if lack of enzyme G6PDH then little NADPH
  • this cuazes heniz bodies due to inappropriate disulfide bonds
  • break down of these red blood cells in liver
  • increased bilirubin in liver
  • jaundice
  • anemia due to increased rat of breakdown od RBC
52
Q

Why could there be reduced levels of G6PDH in person

A

genetic?

would be low in all tissues of the body if its genetic

53
Q

main role of glucose 6 phosphate dehydrogenase

A
  • regenerates NADPH
  • pentose phosphate pathway to make ribose

MEH unit (6 decks)

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