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MEH * > S1 Alcohol Metabolism and Oxidative Stress > Flashcards

S1 Alcohol Metabolism and Oxidative Stress Flashcards

1
Q

What organ metabolises most of the alcohol? How else is alcohol excreted?

A

The liver (over 90%)

Passively in urine and on breath

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2
Q

What enzymes are involved in alcohol oxidation?

A
  1. Alcohol dehydrogenase (alcohol/ethanol to acetaldehyde)

2. Aldehyde dehydrogenase (acetaldehyde to acetate)

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3
Q

What co-enzyme is used in alcohol metabolism?

A

NAD+ to NADH

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4
Q

What accumulation of an intermediate in alcohol metabolism causes a hangover?

A

Acetaldehyde

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5
Q

What is acetate used to produce?

A

Conjugated with coenzyme A to form acetyl CoA

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6
Q

Has aldehyde dehydrogenase got a low or high Km for acetaldehyde?

A

Low

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7
Q

What can cause liver damage linked to alcohol consumption?

A
  1. Accumulation of acetaldehyde

2. Changes in NADH and acetyl-CoA leads to changes in liver metabolism

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8
Q

What two things does alcohol oxidation lead to an increase/decrease in?

A
  1. Decrease in NAD+/NADH ratio

2. Increase in Acetyl-CoA

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9
Q

What does a decrease in NAD+/NADH ratio lead to (linked to alcohol consumption)?

A
  • inadequate NAD+ for conversion of lactate to pyruvate so lactate accumulates in the blood - lactic acidosis or urate crystals accumulate in tissues causing gout (as reduced uric acid excretion in kidneys)
  • inadequate NAD* for glycerol metabolism, gluconeogenesis decreases, hypoglycaemia
  • inadequate NAD+ for fatty acid deoxidation, increased triacylglycerol synthesis, leads to a fatty liver
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10
Q

What does a increased Acetyl-CoA lead to (related to alcohol consumption)?

A
  • increased synthesis of fatty acids and ketone bodies leads to an increase in triacylglycerol synthesis and hence a fatty liver
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11
Q

What is disulfiram?

A

A drug used in the treatment of alcohol dependence

It inhibits aldehyde dehydrogenase, leading to a build up of acetaldehyde causing hangover symptoms

The idea is to stop someone from wanting to drink

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12
Q

What are ROS and RNS?

A

Reactive Oxygen Species

Reactive Nitrogen Species

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13
Q

Name some diseases that can be caused by oxidative stress (9 items):

A
  1. CVS disease
  2. Alzheimer’s
  3. Crohn’s
  4. COPD
  5. Ischaemia
  6. Cancer
  7. Pancreatitis
  8. Parkinson’s
  9. MS
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14
Q

What are free radicals?

A

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

They are very reactive

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15
Q

Describe the transfer of “free radicals” in ROS

A

Oxygen —> Superoxide —> Hydrogen peroxide —> Water + Hydroxyl radical —> Water

Each gains one e- (and none, 1 or 2 H+)

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16
Q

Which ROS is the most reactive and damaging?

A

Hydroxyl Radical (OH*)

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17
Q

What are the two RNS?

A

Nitric oxide and peroxynitrite

Superoxide (ROS) can react with nitric oxide (RNS) to produce peroxynitrite

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18
Q

How many unpaired electrons does molecular oxygen have?

A

2 unpaired electrons - biradical

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19
Q

Which ROS isn’t a free radical?

A

Hydrogen peroxide

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20
Q

What two ways do ROS damage DNA?

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

What is a clinical marker present in cells used to measure oxidative damage in DNA?

A

8-oxo-dG

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22
Q

How do ROS damage proteins?

A
  1. ROS reacts with protein backbone - leads to fragmentation and protein degradation
  2. ROS reacts with protein sidechain - leads to modified amino acid, change in protein structure, leads to loss of function and protein degradation or gain of function
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23
Q

How can inappropriate disulphide bonds form due to ROS?

A

ROS takes electrons from cysteines which causes misfolding, crosslinking and disruption of function (due to disulphide bond formation)

24
Q

How do ROS damage lipids?

A

Process is called lipid peroxidation

  1. Free radical extracts H atom from polyunsaturated fatty acid in the membrane lipid
  2. Lipid radical forms (can react with oxygen to form a lipid peroxyl radical
  3. A chain reaction is caused as lipid peroxyl radical extracts H from nearby fatty acids
  4. The hydrophobic environment of the bilateral is disrupted and membrane integrity fails - cell damage
25
Q

What are some endogenous sources of biological oxidants?

A
  • ETC
  • Nitric oxide syntheses
  • NADPH oxidases
26
Q

What are some exogenous sources of biological oxidants?

A
  • Radiation (cosmic, UV, xrays)
  • Pollutants
  • Drugs (primaquine)
  • Toxins (herbicide)
27
Q

How is the ETC a source of ROS?

A
  • NADH and FADH2 supply electrons from metabolic substrates
  • electrons pass through ETC and reduce oxygen to form water
  • sometimes electrons can accidentally escape the chain and react with dissolved oxygen to form superoxide
28
Q

What does nitric oxide synthase (NOS) do?

A

Converts arginine into citrulline + NO* (NADPH —> NADP+)

29
Q

What are the three types of nitric oxide synthase?

A
  1. iNOS - inductively NOS - produces high NO concs in phagocytes for direct toxic effect e.g. immune response
  2. eNOS - endothelial NOS - involved in signalling - e.g. vasodilation
  3. nNOS - neuronal NOS - involved in signalling e.g. neurotransmission
30
Q

What can NO* be used as?

A

A signalling molecule - vasodilation, neurotransmission, S-Nitrosylation

It is toxic at high levels

31
Q

What is respiratory burst?

A

The rapid release of superoxide and hydrogen peroxide from phagocytic cells

ROS and peroxynitrite destroy invading bacteria - part of the antimicrobial defence system

32
Q

How is susceptibility to bacterial infections enhanced (linked to ROS)?

A

Genetic defects in NADPH oxidase complex

33
Q

What is superoxide dismutase (SOD)? What are the isoenzymes?

A

Converts superoxide to hydrogen peroxide and oxygen.

It is the primary defence because superoxide is a strong initiator of chain reactions

  1. Cu+—Zn2+ cytosolic
  2. Cu+ —Zn2+ extracellular
  3. Mn2+ mitochondria
34
Q

What is catalase?

A

A widespread enzyme that converts hydrogen peroxide to water and oxygen.

Important in immune cells to protect against oxidative burst.

35
Q

How does glutathione donate electrons to ROS?

A
  1. In the reduced form (GSH), glutathione donates electron from the thiol group on cysteine to ROS - making it unreactive.
  2. This causes GSH to react with another GSH to form GSSG (oxidised form) - forms a disulphide bond
36
Q

How is GSSH converted back to GSH?

A

Reduced back to GSH by glutathione reductase and requires NADPH (NADPH —> NADP+) - transfer of electrons from NADPH to disulphide bond

37
Q

What pathway do you get NADPH from?

A

Pentose phosphate pathway

38
Q

What type of molecule is glutathione?

A

A tripeptide (made up of glycine, cysteine and glutamate)

39
Q

What is NADPH required for?

A
  1. Reducing power for biosynthesis
  2. Maintenance of GSH levels
  3. Detoxification reactions
40
Q

What two products do you get from the pentose phosphate pathway?

A
  1. NADPH

2. C5-sugar ribose

41
Q

What is the rate limiting enzyme in the pentose phosphate pathway?

A

Glucose 6-phosphate dehydrogenase (G6PDH)

42
Q

What do free radical scavengers do?

A

Reduces free radical damage by donating hydrogen atom and electrons to free radicals in a non-enzymatic reaction

43
Q

What are some examples of free radical scavengers?

A
  1. Vitamin E - protection against lipid peroxidation
  2. Vitamin C - regenerates reduced form of vitamin E
  3. Carotenoids
  4. Flavonoids
  5. Uric acid
  6. Melatonin
44
Q

Describe galactosaemia:

A
  1. Enzyme in galactose metabolism is deficient (galactokinase, uridyl-transferase, UDP-galactose epimerase
  2. So built up galactose converts to galactitol by enzyme aldose reductase (involves oxidation of NADPH)
  3. Given increased aldose reductase activity, NADPH is used up so there are compromised defences against ROS damage - protein in lens of eye denatured leading to cataract formation
45
Q

What does G6PDH deficiency cause?

A
  1. Limits the amount of NADPH
  2. So less GSH (not converted back to GSH from GSSG) means less protection against oxidative stress damage
  3. This can lead to lipid peroxidation - cell membrane damage
    And protein damage - heamolysis
46
Q

What things can cause oxidative stress?

A
  1. Infection
  2. Drugs
  3. Broad beans (fava beans)
47
Q

What are Heinz bodies? What do they cause?

A

Oxidative stress leads to protein damage which leads to aggregates of cross-linked Hb (disulphide bond formation in Hb (GSSG)). These aggregates are called Heinz bodies.

They bind to the cell membrane altering the rigidity and lead to increased mechanical stress when cell moves through capillaries.

48
Q

What organ removes Heinz bodies?

A

The spleen

Removes them resulting in “blister cells”

49
Q

Why do RBC need lots of NADPH?

A

RBC’s carry oxygen so are at an increased risk of oxidative stress

50
Q

How is paracetamol metabolised normally?

A

Paracetamol —> glucuronide + sulphate

51
Q

What is produced during paracetamol metabolism is the levels of the drug are high?

A

Toxic, NAPQI, which can lead to oxidative damage of liver cells - lipid peroxidation, damage to proteins, damage to DNA.

NAPQI can also go onto produce glutathione which is also aided by acetylcysteine as low glutathione levels lead to oxidative damage.

52
Q

What does U/g tissue mean?

A

Micromoles per min per gram of tissue

53
Q

What is the product of Hb breakdown?

54
Q

What does high levels of bilirubin cause?

55
Q

Why does adipose tissue have higher G6DPH activity than some tissues?

A

ROS can cause damage to lipids by lipid peroxidase

56
Q

Why does skeletal muscle have low G6DPH activity?

A

No need for lipids/G6PDH/NADPH/etc as uses glycolysis

57
Q

What does the brain need G6PDH?

A

Lipid synthesis occurs for myelination

MEH * (22 decks)

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