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Metabolism, Endocrinology and Haematology > Alcohol Metabolism and Oxidative Stress > Flashcards

Alcohol Metabolism and Oxidative Stress Flashcards

1
Q

Describe the energy content of alcohol

A

High energy content (29KJ/g) but not as high as fat.

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2
Q

Where is alcohol metabolised?

A

>90% by the liver, the remainder is passively excreted in the urine or breath.

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3
Q

What are the stages of alcohol metabolism?

A

Normal pathway (see image)

Smaller amount of alcohol can be oxidised by CYP2E1 (P450 family member) or by catalase in the brain.

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4
Q

What is acetate converted to?

A

Acetyl coA to be used in the TCA/Krebs cycle or for fatty acid synthesis.

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5
Q

What is the recommended units of alcohol per week?

A

14 units over at least 3 days for both men and women.

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6
Q

What is the rate of alcohol metabolism?

A

One unit of alcohol = 8g

1 unit = half a pint of normal strength beer or a small glass of wine

Eliminated at rate of ~7g per hour following zero order kinetics.

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7
Q

When does liver damage occur?

A
  • Acetaldehyde toxicity is kept minimal by aldehyde dehydrogenase which has a low Km for acetaldehyde.
  • Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde accumulation to cause liver damage.
  • Excess NADH and acetyl-CoA can lead to changes in liver metabolism
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8
Q

What are the stages of alcohol-related liver disease (ALRD)?

A

Alcoholic fatty liver disease

  • build-up of fats in the liver
  • asymptomatic
  • reversible

Alcohol hepatitis

  • Mallory’s hyaline body, swelling and inflammation
  • Symptoms: feeling unwell, hepatomegaly and ascites.
  • Reversible

Cirrhosis

  • Extensive scarring
  • Irreversible
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9
Q

How does alcohol consumption lead to lactic acidosis and urate crystals/gout?

A

Lactic Acidosis

  • Decrease in NAD+/NADH ratio
  • Lactate cannot be converted to pyruvate and accumulates in the blood.
  • Lactic acidosis lowering blood pH

Urate Crystals

  • Linked to accumulation of lactate
  • Lactate and uridyl acid hare the same transporter in the kidney
  • Kidneys ability to excrete uric acid is reduced
  • Urate crystal accumulate in tissues producing gout.
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10
Q

How does alcohol metabolism lead to hypoglycaemia?

A
  • Reduced NAD+/ NADH ratio
  • inadequate NAD+ for glycerol metabolism
  • deficit in gluconeogenesis
  • hypoglycaemia
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11
Q

How does alcohol metabolism lead to fatty liver?

A
  • Decrease in NAD+/NADH ratio
  • Insufficient NAD+ for fatty acid oxidation and increased acetyl-CoA
    • higher acetyl-CoA causes increase synthesis of fatty acids and ketone bodies
  • Higher synthesis of fatty acids and inadequate NAD+ leads to increased synthesis of triacylglycerol causing a fatty liver.
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12
Q

What is disulfiram?

A
  • Treatment for chronic alcohol dependence used alongside other treatment.
  • Works as an inhibitor of aldehyde dehydrogenase to accumulate acetaldehyde causing symptoms of a hangover.
  • Low compliance as pts won’t take a drug that makes them feel sick.
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13
Q

What is oxidative stress?

A

When the ratio of free radicals and antioxidants/free radical scavengers have an imbalance to favour free radicals.

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14
Q

What diseases are related to 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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15
Q

What are free radicals?

A

an atom or molecules that contain one or more unpaired electrons to produce highly reactive properties of that species.

Damage is caused by acquiring electrons from surrounding tissue thus producing a second free radical causing propagating damage.

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16
Q

How are superoxide radicals produced?

A

Electrons occasionally escape the ETC and react with dissolved O2 to form superoxide (O2•-).

17
Q

What are reactive oxygen species?

A
  • Superoxide (O2•-) - electron added from the ETC to molecular oxygen)
  • Hydrogen peroxide (H2O2) - not a free radical but can react with Fe2+ to produce free radicals
  • Hydroxyl Radical (OH•) -most damaging free radical
18
Q

What are the reactive nitrogen species?

A
  • Nitric oxide (NO•)
    • Produced by nitric oxide synthase when converting arginine to citrulline
      • iNOS: inducible. Produces high [NO•] in phagocytes for toxic effects
      • eNOS: endothelial. Produces NO• for signalling
      • nNOS: neuronal. Produces NO• for signalling
    • At high levels has toxic effects
    • At small concentrations used as signalling for
      • Vasodilation
      • Neurotransmission
      • S-nitrosylation
  • Peroxynitrite (ONOO-) - when nitric oxide and superoxide react. Not a free radical but a powerful oxidant that can damage cells.
19
Q

What does ROS damage?

A

DNA

  • reacts with a base or a sugar
  • damages bases and strands
  • causes a mutation that can be oncogenic

Proteins

  • reacts with backbone or side chain (cysteine)
    • backbone results in protein degradation
    • sidechain results in a structural change
      • loss of function
      • gain of function
      • protein degradation

Lipids

  • reacts with polyunsaturated fatty acid in membrane lipid
  • chain reaction/ propagation disrupts the hydrophobic environment of membrane bilayer failing membrane integrity
20
Q

How are disulphide bonds disrupted by ROS?

A
  • Disulphide bonds mainly found in secreted proteins or extracellular domains
  • ROS removes electrons from thiol groups of cysteine residues
  • disulphide bonds form between cysteine residues
  • inappropriate disulphide bond formation occurs
    • misfolding and cross-linking (tertiary structure)
    • disruption of protein function occurs
21
Q

What are the sources of biological oxidants?

A

Endogenous

  • ETC (main source)
  • Peroxidases
  • Nitric oxide synthases
  • Lipoxygenases
  • NADPH oxidases
  • Xanthine oxidase
  • Monoamine oxidase

Exogenous

  • Radiation
    • cosmic rays
    • UV light
    • X-rays
  • Pollutants
  • Drugs
    • primaquine (antimalarial) - G6PD deficinency screen before prescribing
  • Toxins
    • paraquat (herbicide)
22
Q

What is respiratory burst?

A

The rapid release of superoxide and hydrogen peroxide from phagocytic cells (neutrophils and monocytes) to destroy invading bacteria.

  • peroxynitrite (from O2•- and NO•) and hypochlorite destroy bacteria as part of the antimicrobial defence system
  • NADPH oxidase is a membrane-bound complex of phagocytes that produces the superoxide for the microbial defence
23
Q

What are chronic granulomatous diseases (CGD) and their aetiology?

A

Inherited primary immunodeficiency disease (PIDD) caused by genetic defects in NADPH oxidase complex. Individuals have an enhanced susceptibility to bacterial infections:

  • Atypical infections
  • Pneumonia
  • Abscesses
  • Impetigo
  • Cellulitis
24
Q

What are the cellular defences against oxidative stress?

A

Superoxide dismutase (SOD)

  • converts superoxide to hydrogen peroxide and oxygen
  • primary defence
  • 3 isoenzyme
    • cytosolic
    • extracellular
    • mitochondria

Catalase

  • converts hydrogen peroxide to water and oxygen
  • wide spread enzyme; vital in immune cells to protect against oxidative burst
  • decline in hair follicles causes grey hair

Glutathione (GSH and GSSG)

  • tripeptide synthesised by the body
  • reforms disrupted disulphide bonds using electrons from NADPH from the pentose phosphate pathway
  • glutathione reductase requires selenium

Free Radical Scavengers - (donate H in nonenzymatic reaction)

  • Vitamin E (alpha-tocopherol)
    • lipid soluble
    • protects against lipid peroxidation
  • Vitamin C (ascorbic acid)
    • water soluble
    • regenerates the reduced form of Vit E
  • Carotenoids
  • Uric acid
  • Flavenoids
  • Melatonin
25
Q

Describe the pentose phosphate pathway and the significance it has to oxidative stress.

A
  • Glucose-6-phosphate is the input
  • Key source of NADPH for:
    • reduction reactions in biosynthesis
    • maintaining GSH levels
    • detoxification reactions
  • Produces a 5 carbon sugar (ribose 5-phosphate) for:
    • nucleotides
    • DNA and RNA
  • Does not synthesise ATP
  • Produces CO2
  • Rate limiting glucose 6-phosphate dehydrogenase
    • deficiency of G6PD = less protection from oxidative stress
26
Q

What is galactosemia?

A

An autosomal recessive metabolic disorder that causes an increase in of galactose in the blood. Orchestrated by a deficiency in one of three enzymes:

  • galactokinase
  • uridyl transferase
  • UDP-galactose epimerase (more rare)

Features of galactosaemia:

  • consumption of excessive NADPH
    • leaves cells are comprised to oxidative damage
  • cataracts
  • hepatomegaly and cirrhosis
  • renal failure
  • vomiting
  • seizure and brain damage
  • hypoglycaemia
27
Q

How does galactosemia cause cataracts?

A
  • Excess galactose is converted to galactitol via aldose reductase and NADPH
  • Galactitol increases osmotic pressure and causes water to be drawn into the lens
    • damage and stretches lens fibres
  • Compromised defences again ROS (less NADPH) denatures crystallin protein in lens of eye = cataracts
28
Q

Describe G6PDH deficiency and it’s relation to oxidative stress

A

an X linked recessive disease primarily affecting males. A genetic mutation causes decreased G6PDH activity limiting the amounts of NADPH:

  • NADPH reduces oxidised glutathione (GSSG) back to reduced glutathione (GSH)
    • lower GSH = less protection against oxidative stress

Oxidative stress + G6PDH deficiency =

  • Lipid peroxidation
    • cell membrane damage, deformation causes mechanical stress
  • Protein damage
    • aggregates of cross-linked haemoglobin (Heinz bodies) causing haemolysis
29
Q

What are Heinz bodies?

A
  • Dark staining within RBS from precipitating haemoglobin
  • Aggregates bind to cell membrane altering rigidity
    • when RBC squeeze through small capillaries there is increased mechanical stress on the RBC causing them to lyse (haemolysis)
  • Spleen removes bound Heinz bodies causing ‘blister cells’ (RBC with peripherally located vacuole)
  • Clinical sign of G6PDH deficiency
30
Q

Describe the metabolism of paracetamol (acetaminophen) and how an overdose is resolved.

A
  • Metabolised in hepatocytes

At prescribed dose:

  • metabolised safely by conjugation with glucuronide and sulphate to produce non-toxic products

Overdose:

  • enzyme organising glucuronidation and sulphation becomes saturated
  • toxic levels of NAPQI (paracetamol metabolite) accumulate
    • normally safe when bound to glutathione but in excess production of NAPQI glutathione is depleted.
  • causes oxidative damage to hepatocyte (lipid peroxidation, protein and DNA damage)

Treatment

  • N-acetylcysteine (NAC)
    • replenishes glutathione levels
    • excess NAPQI has enough glutathione to bind to and be excreted safely

Metabolism, Endocrinology and Haematology (5 decks)

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