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MEH > Alcohol Metabolism & Oxidative Stress > Flashcards

Alcohol Metabolism & Oxidative Stress Flashcards

1
Q

Aldehyde dehydrogenase has a low km for acetylaldehyde, why is this good?

A

Km = 1/2 vmax (speed). Low Km means the toxic acetyladldehyde is converted to less damaging acetate more quickly.

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2
Q

what do excess NADH and acetyl coA lead to?

A

Changes in liver metabolism:
Fatty liver (increased Acetyl coA = fatty liver)
Alcoholic hepatitis
Alcoholic cirrhosis

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3
Q

What is the classic treatment for alcoholics?How does it work?

A

Disulfiram- It inhibits the enzyme aldehyde dehydrogenase leading to a build up of acetylaldehyde which produces hangover symptoms. Now there is a negative association with alcohol.

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4
Q

Why do reactive oxygen species (ROS) and reactive nitrogen species (RNS) do to cells?

A

Damages nuclei acids, proteins and lipids.

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5
Q

What is the link between oxidative stress and disease?

A

When cell defences such as antioxidants do not counterbalance oxidative stress can increase the risk of many disease states (Rheumatoid arthritis, Parkinson’s, Alzheimer’s.

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6
Q

What is a free radical?

A

An atom/ molecule with at least one unpaired electron

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7
Q

How do free radicals cause damage?

A

They are reactive. They ‘steal’ the electrons of other atoms/ molocules in order to provide an electron for their unpaired electron(s). This action usually generates another radical - generating more damage.

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8
Q

Molecular oxygen is what kind of radical?

A

Biradical (2 unpaired electrons)

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9
Q

How is superoxide formed?

A

Adding one electron to molecular oxygen

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10
Q

How can hydrogen peroxide be damaging?

A

Not a free radical but can react with iron (Fe) to produce free radicals. It is readily diffusable.

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11
Q

What is the most damaging radical?

A

Hydroxyl - reacts with almost anything!

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12
Q

What can a hydroxyl radical be reduced to form?

A

Water

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13
Q

Super oxide reacts with what to produce peroxynitrite?

A

Nitric oxide

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14
Q

Why is peroxynitrite worrying?

A

Not a free radical but it is a powerful oxidant that can damage cells.

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15
Q

How can ROS damage to DNA lead to cancer?

A

Can react with DNA 1. A base —> can lead to mispairing and potential mutation —>potential for cancer or
2. A deoxy/ribose sugar —>causes strand break and potential mutation on repair —> potential for cancer

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16
Q

How can ROS damage to proteins lead to issues?

A

Damages

  1. Backbone - fragmentation –> protein degraded
  2. Sidechain –> failure in repair can lead to mutation and to cancer OR to a change in protein structure (modified amino acid) such as a disulphide bond and either a loss/ gain of function or protein degradation.
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17
Q

When a carbon is bonded to a SH the group is called a ______ group

A

Thiol

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18
Q

Why can a ROS cause damage if takes electrons from cysteine?

A

Can cause inappropriate disulphide bond formation from cysteines causing misfiling, cross linking or disruption of function.

19
Q

Why can lipid peroxidation be harmful to cell membranes?

A

Composed of phospholipids. The bilayer can be disrupted by lipid peroxidation and it’s integrity fails.

20
Q

Explain the process of lipid peroxidation

A
  • Free radical extracts hydrogen from a polyunsaturated fatty acid
  • lipid radical formed which can react with oxygen to form a lipid peroxyl radical
  • chain reaction formed as lipid peroxyl radical extracts H from nearby fatty acid
  • hydrophobic environment of bilayer disrupted and membrane integrity fails.
21
Q

Name 3 sources of biological oxidants in the human body

A
  1. Electron transport chain
  2. Nitric oxide synthases
  3. NADPH oxidases
22
Q

How are free radicals created from the ETC?

A

Occasionally electrons escape ETC and react with dissolved o2 to form superoxide

23
Q

3 different types of nitric oxide synthases?

A
  1. iNOS Inducible nitric oxide synthase (phagocytes use for direct toxic effect)
  2. eNOS Endothelial nitric oxide synthase (signalling- used in vasodilation of blood vessels)
  3. nNOs Neuronal nitric oxide synthase (signalling- neurotransmission)
24
Q

What is a respiratory burst?

A
  • Rapid release of superoxide and hydrogen peroxide from phagocytotic cells (neutrophils and monocytes).
  • ROS and peroxynitrite destroy invading bacteria
25
Q

Describe the biochemical reactions involved in a respiratory burst

A

Phagocytes contain iNOS and NADPH oxidase.

  1. NADPH oxidase reduces O2 to form superoxide. This can then gain hydrogen and electrons –>hydrogen peroxide.
    Myleoperoxidase released from cells reacts with hydrogen peroxide to produce bleach to kill cells.
  2. iNOS creates nitrous oxide –> reacts superoxide to make peroxynitrite –> kills bacteria.
26
Q

What is Chronic granulomatous disease?

A

Genetic defect in NADPH oxidase complex

  • enhanced susceptibility to bacterial infections
  • pneumonia
  • abcesses
  • Cellulitis
27
Q

Name an important cellular defence that converts superoxide to water and oxygen

A

SOD
-Converts superoxide to hydrogen peroxide and oxygen
-primary defence as superoxide is good as starting chain reactions
-3 isoenzymes:
-mitochondira -cystolic -extracellular
Catalase
-Convers hydrogen peroxide to water and oxygen
–widespread enzyme. Important in immune cells to protect vs oxidative burst
-grey hair!

28
Q

How does glutathione work as a cellular defence?

A

-protects vs oxidative damage
-Thiol group of Cys donates e- to ROS to stop from damaging the body
-GSH reacts another GSH to form disulphide (GSSG) this is catalysed by glutathione peroxidase.
CONVERTS back:
Glutathione reductase catalyses transfer of electrons from NADPH to disulphide bond to reduce GSSG.

29
Q

Which pathway in metabolism is an important source for NADPH and is therefore important for preventing oxidative damage?

A

Pentose Phosphate Pathway

30
Q

Glutathione peroxidase requires what nutrition to continue working?

A

Selenium

31
Q

Where does pentose phosphate pathway start from?

A

glucose-6-phosphate

32
Q

Why is NADPH required in the body?

A
  • reducing power for biosynthesis
  • maintenance of GSH levels
  • detoxification reactions
33
Q

What is produced via pentose phosphate pathway?

A
  • reducing power
  • C5 sugar ribose for creation nucleotides, DNA, RNA
  • NO ATP
  • CO2 produced
34
Q

Rate limiting enzyme in PPP?

A

Glucose 6-phosphate dehydrogenase

35
Q

What is the role of free radical scavengers?

A

Donate hydrogen atoms (and its electron) to free radical

The reaction is NONENZYMATIC

36
Q

Why is vitamin E important in terms of preventing damage to membranes?

A
  • radical scavenger
  • lipid soluble (so can reach cell membranes)
  • important for protection against lipid per oxidation
37
Q

Why is vitamin C important for preventing radical damage?

A

-water soluble -important role in regenerating reduced form of vitamin E

38
Q

What can lead to a cataract?

A

–> galactosaemia –> increased activity of aldose reductase consumes excess NADPH –> compromised defences against ROS damage –> crystallin protein in lens of eye denatured

39
Q

Why can a G6PDH deficiency result in oxidative damage?

A

G6PDH key enzyme in PPP.
PPP used to create NADPH.
NADPH regenerates glutathione.
Lack glutathione = less protection from oxidative stress.
-Lipid peroxidation –> cell membrane damage
-protein damage –> aggregates of cross-linked haemoglobin –> Heinz bodies

40
Q

Why are Heinz bodies an issue for RBC?

A
  • bind to cell membrane and alter rigidity
  • increase likelihood of mechanical stress on RBC
  • Increased likelihood haemolysis
41
Q

What can be a clinical sign in RBC of G6PDH deficiency?

A

blister cells created by spleen removing Heinz bodies

42
Q

Why is excess consumption of paracetamol harmful?

A

-cannot be converted into normal metabolites Glucuronide and Sulphate as that pathway is saturated
-creates NAPQI - toxic
Glutathione can take e- to make less toxic –> using glutathione stores up!

43
Q

How does a paracetamol overdose damage hepatocytes?

A
  • lipid peroxidation
  • damage to proteins
  • damage to DNA
44
Q

What treatment for overdose paracetamol and how does it work?

A
  • Acetylcysteine

- Replenishes glutathione levels

MEH (3 decks)

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