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Semester 2 - MEH > 1. Alcohol metabolism and oxidative stress > Flashcards

1. Alcohol metabolism and oxidative stress Flashcards

1
Q

why is it useful to metabolise alcohol for energy?

A

Alcohol has a high energy content. higher than carbohydrates, less than fat.

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2
Q

where in the body does alcohol metabolism occur?

A

Most (>90%) alcohol is metabolised by liver

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3
Q

what happens to the remainder of alcohol that is not metabolised?

A

Remainder excreted passively in urine and on breath.

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4
Q

what are the 2 enzymes involved in alcohol metabolism?

A

alcohol dehydrogenase

aldehyde dehydrogenase.

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5
Q

give the process of alcohol metabolism

A

• Alcohol(ethanol) oxidised by alcohol dehydrogenase to acetaldehyde (reducing NAD to NADH) and then to
acetate by aldehyde dehydrogenase(reducing NAD to NADH).
• Acetate converted to acetyl~CoA by conjugation to coenzyme A and then used in TCA cycle or for fatty acid synthesis

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6
Q

other than the alcohol dehydrogenase pathway, which other 2 pathways can metabolise smaller amounts of alcohol?

A

• Smaller amounts of alcohol can also be oxidized by the cytochrome P4502E1 enzyme (CYP2E1), or by catalase in brain.

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7
Q

what are the recommended alcohol limits for both men and women?

A

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

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8
Q

what does ethanol elimination follow?

A

zero order kinetics - the rate of elimination is constant despite the volume of alcohol intake

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9
Q

what is the rate of alcohol metabolism?

A

Eliminated at rate of ~7g per hour

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10
Q

why is Acetaldehyde bad and what does its accumulation result in?

A

Acetaldehyde is a toxic metabolite. Accumulation of acetaldehyde plus dehydration (which is caused by ethanol inhibiting secretion of ADH) causes “Hangover”

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11
Q

what keeps Acetaldehyde toxicity to a minimum?

A 
Acetaldehyde toxicity normally kept to a minimum by
aldehyde dehydrogenase (low Km for acetaldehyde so acts readily and quickly)
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12
Q

how can alcohol abuse result in liver damage?

A

• Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde accumulation to cause
liver damage
• Excess NADH and Acetyl-CoA lead to changes in liver metabolism causing:
- “Fatty liver”
- Alcoholic hepatitis
- Alcoholic cirrhosis

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13
Q

how does excessive alcohol oxidation result in lactic acidosis?

A
  • excessive alcohol oxidation causes decrease in NAD concentration which means there is Inadequate NAD+ for conversion of lactate to pyruvate.
  • Lactate accumulates in blood causing lactic acidosis
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14
Q

how does excessive alcohol oxidation result in gout?

A
  • excessive alcohol oxidation causes decrease in NAD concentration which means there is Inadequate NAD+ for conversion of lactate to pyruvate.
  • Lactate accumulates in blood.
  • Kidney’s ability to excrete uric acid reduced.
  • Urate crystals accumulate in tissues producing gout
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15
Q

how does excessive alcohol oxidation result in Hypoglycaemia?

A
  • excessive alcohol oxidation causes decrease in NAD concentration which means there is Inadequate NAD+ for glycerol metabolism
  • leads to Deficit in gluconeogenesis which can result in Hypoglycaemia

The low NAD+ level combined with the inability
of the liver cells to use lactate and glycerol means that
gluconeogenesis cannot be activated and fasting hypoglycaemia may become a serious problem. The poor dietary habits of the alcoholic may also contribute to the hypoglycaemia as liver glycogen levels tend
to be low.

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16
Q

how does excessive alcohol oxidation result in Fatty liver?

A
  • excessive alcohol oxidation causes decrease in NAD concentration which means there is Inadequate NAD+ for fatty acid oxidation
  • this leads to Increased synthesis of Triacylglycerol
  • excessive alcohol oxidation can also result in Increased Acetyl-CoA which results in Increased synthesis of fatty acids and ketone bodies
  • this also causes Increased synthesis of Triacylglycerol
  • the Increased synthesis of Triacylglycerol, combined with Lower lipoprotein synthesis(due to the limited protein synthesis in the liver) results in fatty liver as the fat cannot be packed into lipoproteins to be transported out of the liver
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17
Q

what is disulfaram and how does it work?

A

• Disulfiram is a drug that can be used as an adjunct in the treatment of chronic alcohol dependence.
• It is an inhibitor of aldehyde dehydrogenase
• this means that acetaldehyde can’t be converted to acetate
• If patient drinks alcohol acetaldehyde will
accumulate causing symptoms of a ‘hangover’
• this acts as a pavlovian/ classical conditioning which causes the association of alcohol with feeling sick

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18
Q

what is oxidative stress?

A

Oxidative stress is an imbalance between free radicals and antioxidants(cell defences) in your body. There is either too many free radicals or if the defences are compromised

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19
Q

list the diseases caused by oxidative stress

A 
Cardiovascular disease
Alzheimer’s disease
Rheumatoid arthritis
Crohn’s disease
COPD
Ischaemia/reperfusion injury
Cancer
Pancreatitis
Parkinson’s disease
Multiple sclerosis
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20
Q

what are free radicals?

A
  • Electrons of atoms, molecules & ions usually associate in pairs. Each pair moves within a defined region of space (an orbital).
  • A free radical is an atom or molecule that contains one or more unpaired electrons and is capable of independent (“free”) existence
  • A superscript dot used to denote free radical (e.g.OH)
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21
Q

why are free radicals dangerous?

A
  • Free radicals (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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22
Q

what are the reactive oxygen species (ROS) and how are they formed?

A
  • Molecular oxygen is a biradical. it is a free radical but is stable as the 2 unpaired electrons are in different orbitals
  • Superoxide(free radical) is Produced by adding electron to molecular oxygen. Also Important source of other ROS.
  • Hydrogen peroxide H2O2 is produced by adding 2H+ and e- to superoxide. Not a free radical but can react e.g. with Fe2+ to produce free radicals. Readily diffusible.
  • adding H+ and e- to hydrogen peroxide forms water and hydroxyl radical. hydroxyl radical is the Most reactive and damaging free radical. Reacts with anything!
  • when hydroxyl radical reacts, it takes an electron from another molecule, damaging the molecule. water is formed by the addition of e- and H+ to hydroxyl radical
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23
Q

what are the reactive nitogen species (RNS) and how are they formed?

A
  • reactive nitrogen species fall under the umbrella term of reactive oxygen species
  • Superoxide can react with nitric oxide( a free radical) to produce peroxynitrite
  • Peroxynitrite is not itself a free radical, but is a powerful oxidant that can damage cells
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24
Q

what are the two main types of ROS damage to DNA?

A

• ROS reacts with base
- Modified base can lead to mispairing and mutation
• ROS reacts with sugar (ribose or deoxyribose)
- Can cause strand break and mutation on repair

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25
Q

what is the possible effect of ROS damage to DNA?

A
  • the reaction of the ROS with DNA results in DNA damage.
  • Failure to repair this damage can lead to a mutation that can be permanently embedded in DNA.
  • This can lead to cancer
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26
Q

what is the clinical function of 8-oxo-dG?

A

8-oxo-dG is a mutated form of the Deoxyguanosine molecule.
when there are high levels of oxidative stress, it is abundant in the body.
The amount of 8-oxo-dG present in cells can be used as measurement of oxidative damage

27
Q

which components of the protein can be damaged by ROS?

A

backbone and side-chain

28
Q

describe what happens when the ROS damages protein backbone

A

If the ROS reacts with the backbone of the protein, it can cause fragmentation. This fragmentation can then lead to protein degradation

29
Q

describe what happens when the ROS damages protein side chains?

A 
If the ROS reacts with the sidechain of the protein, it can result in a modified amino acid which means formation of:
• Carbonyls
• Hydroxylated adducts
• Ring opened species
• Dimers (e.g. di-tyrosine)
• Disulphide bond (Cys)

this can lead to change in protein structure which could mean there is a loss of function or gain of function. If there is loss of function, it results in protein degradation.

30
Q

what is the role of disulphide bonds?

A

Play important role in folding and stability of some proteins (usually secreted proteins or in extracellular domains of membrane proteins)

31
Q

where do disulphide bonds form?

A

Formed between thiol groups of cysteine residues

32
Q

what can cause inappropriate disulphide bond formation?

A

Inappropriate disulphide bond formation can

occur if ROS takes electrons from cysteines

33
Q

what are the effects of inappropriate disulphide bond formation?

A

misfolding, crosslinking and

disruption of function (e.g. enzyme)

34
Q

describe ROS damage to lipids

A

lipid peroxidation:
• Free radical (e.g. OH) extracts hydrogen atom from a polyunsaturated fatty acid in membrane lipid
• Lipid radical formed which can react with oxygen to form a lipid peroxyl radical
• Chain reaction formed as lipid peroxyl radical extracts hydrogen form nearby fatty acid
• Hydrophobic environment of bilayer disrupted and membrane integrity fails

35
Q

what are the endogenous sources of biological oxidants?

A
  • Electron transport chain
  • Nitric oxide synthases
  • NADPH oxidases
36
Q

what are the exogenous sources of biological oxidants?

A 
• Radiation
Cosmic rays
UV light
X-rays
• Pollutants
• Drugs
Primaquine (anti-malarial)
• Toxins
Paraquat (herbicide)
37
Q

how can the electron transport chain act as a source of ROS?

A
  • NADH and FADH2 supply electrons (e−) from metabolic substrates
  • e − 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 which can eventually form hydroxyl radical which can damage DNA, proteins or lipids
38
Q

what is the function of Nitric oxide synthases

(NOS)?

A

these enzymes are used to convert the enzyme arginine to citrulline and nitric oxide. It involves the oxidation of NADPH to NADP

39
Q

what are the 3 types of Nitric oxide synthase

(NOS)?

A
  • iNOS: Inducible nitric oxide synthase. Produces high NO concentrations in phagocytes for direct toxic effect.
  • eNOS: Endothelial nitric oxide synthase (produces Signalling NO)
  • nNOS: Neuronal nitric oxide sytnthase (produces Signalling NO)
40
Q

what are the 2 functions of nitric oxide?

A
  1. Toxic effects at high levels
  2. Signalling molecule:
    • Vasodilation
    • Neurotransmission
    • S-Nitrosylation
41
Q

what is respiratory burst?

A

• Rapid release of superoxide & H2O2 from phagocytic

cells (e.g. neutrophils and monocytes)

42
Q

what is the function of respiratory burst?

A
  • ROS and peroxynitrite destroy invading bacteria

* Part of antimicrobial defence system

43
Q

describe what happens during respiratory burst?

A
  • white blood cells have iNOS which produce NO.
  • NADPH oxidase is also present in white blood cells which convert NADPH to NADP and as a by product, convert oxygen to superoxide.
  • the NO and superoxide react to form peroxynitrite which attack the bacteria.
  • the superoxide can also form hydrogen peroxide which reacts with chlorine to form hypochlorite in the presence of myeloperoxidase. the hypochlorite can also attack bacteria.
44
Q

list the 3 types of cellular defences

A
  1. Superoxide dismutase and catalase
  2. Glutathione
  3. Free radical scavengers
45
Q

how can Superoxide dismutase and catalase be used to defend the cell from oxidative stress?

A

• Superoxide dismutase (SOD) Converts superoxide to H2O2 and oxygen
• Primary defence because superoxide is strong
initiator of chain reactions
• Catalase Converts H2O2 to water and oxygen
• Widespread enzyme. Important in immune cells to
protect against oxidative burst

46
Q

what can declining levels of catalase explain?

A

Declining levels in hair follicles with age may

explain grey hair

47
Q

how can glutathione be used to defend the cell from oxidative damage?

A

• glutathione is a Tripeptide synthesised by body to
protects against oxidative damage
• the reduced form of glutathione, GSH, consists of glycine, cystein and glutatamate residues.
• Thiol group of Cys donates e− to ROS in the presence of Glutathione peroxidase. GSH then reacts with another GSH to form disulphide bonds.
The gluitathione is now in its oxidised form, GSSG and the ROS has been converted to water.
• Glutathione peroxidase requires selenium
• GSSG reduced back to GSH by glutathione reductase which catalyses the transfer of electrons from NADPH to disulphide bond (NADPH –> NADP)
• NADPH from pentose phosphate pathway is therefore essential for protection against free radical damage

48
Q

what is the function of the pentose phosphate pathway?

A

important source of NADPH required for:
• reducing power for biosynthesis
• maintenace of GSH levels
• detoxification reactions

produces C5-sugar ribose required for synthesis of:
• nucleotides
• DNA and RNA

49
Q

how can Free radical scavengers be used to defend the cell from oxidative stress?

A

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

50
Q

what are the main free radical scavengers and what are their properties?

A

Vitamin E
(α-tocopherol)
• Lipid soluble antioxidant
• Important for protection against lipid peroxidation

Vitamin C
(Ascorbic acid)
• Water soluble antioxidant
• Important role in regenerating reduced form of Vitamin E

51
Q

what causes galactosaemia? what are its effects?

A

a deficiency in any of the 3 galactose enzymes results in galactose building up and so being converted to galactitol by aldose reductase causing galactosaemia. this process uses up NADPH which compromises defences against ROS damage. It can result in symptoms such as cataracts as the crystallin protein in the lens of the eye is denatured.

52
Q

what is the role of Glucose 6-Phosphate

dehydrogenase(G6PDH )?

A

G6PDH is the first enzyme in the pentose phosphate pathway. it produces NADPH from NADP and 5C pentose phosphates.

53
Q

what are the effects of G6PDH Deficiency ?

A
  • Decreased G6PDH activity limits amount of NADPH
  • NADPH required for reduction of oxidised glutathione (GSSG) back to reduced glutathione (GSH)
  • Lower GSH means less protection against damage from oxidative stress
54
Q

what can cause oxidative stress?

A
  • Infection
  • Drugs (e.g. anti malarial)
  • Broad beans
55
Q

what are the effects of oxidative stress?

A

Lipid peroxidation
• Cell membrane damage
• Lack of deformity leads to mechanical stress

Protein damage
• Aggregates of crosslinked haemoglobin (Heinz bodies)

This can result in Haemolysis

56
Q

why are red blood cells more likely to be affected by C?

A

In RBCs the pentose phosphate pathway is the only source of NADPH so G6PDH Deficiency means the RBCs cannot get any NADPH so cannot return glutathione to its reduced state. Other cells can obtain NADPH from other pathways

57
Q

what are Heinz bodies?

A
  • Dark staining within red blood cells resulting from precipitated haemoglobin
  • Bind to cell membrane altering rigidity
  • Increased mechanical stress when cells squeeze through small capillaries
  • Clinical sign of G6PDH deficiency
58
Q

which organ removes heinz bodies?

A

Spleen removes bound Heinz bodies resulting in “blister cells”

59
Q

where does paracetamol metabolism take place?

A

Hepatocyte

60
Q

describe paracetamol metabolism at normal dosage

A

At prescribed dosage paracetamol can be safely metabolised by conjugation with glucuronide or sulphate

61
Q

describe paracetamol metabolism at high dosage

A

when paracetamol is in excess, the normal metabolism pathways are saturated so is directed down another pathway. With high levels of paracetamol the toxic metabolite NAPQI accumulates. NAPQI is an oxidant which causes Oxidative damage to liver cell
• Lipid peroxidation
• Damage to proteins
• Damage to DNA
To protect against NAPQI, the body uses up glutathione and glutathione depletion can also result in oxidative damage

62
Q

what is the antidote to paracetamol overdose?

A

Acetylcysteine: Antidote acetylcysteine works by replenishing glutathione levels

63
Q

what are the symptoms of haemolysis?

A
  1. Anaemia

Semester 2 - MEH (23 decks)

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