Alcohol Metabolism & Oxidative Stress Flashcards
Describe how alcohol is metabolised
90% met in liver:
1) alcohol is oxidised by alcohol dehydrogenase to acetaldehyde (NAD+ –> NADH)
2) then to acetate by aldehyde dehydrogenase (NAD+ –> NADH),
3) acetate is then converted to acetyl-CoA,
4) used in the TCA cycle or for fatty acid synthesis
What is the recommended alcohol limit for men and women?
14 units over 3 days
What part of alcohol met is toxic and causes hangovers?
Acetaldehyde – accumulation causes hangovers
Explain how alcohol can cause liver damage
Acetaldehyde toxicity normally kept to a minimum by aldehyde dehydrogenase
prolonged excessive alcohol consumption can = acetaldehyde accumulation = liver damage.
Increase in Acetyl-CoA = increased synthesis of fatty acids = fatty liver
Explain the metabolic response to chronic alcohol consumption
Increase in Acetyl-CoA = increased synthesis of fatty acids = fatty liver.
Decrease in NAD+/NADH ratio = low NAD+ for conversion of lactate to pyruvate = lactic acidosis, lactate effects kidneys ability to excrete uric acid = gout.
Low NAD+ = low gluconeogenesis = hypoglycaemia
Explain the mechanism of action of Disulfiram
Inhibits aldehyde dehydrogenase = accum of acetaldehyde = severe hangover = deterrent
What is oxidative stress?
Unbalance between cell damage by ROS/RNS and cell defences = antioxidants, glutathions, superoxide dismutase
What is a free radical?
Atom/molecules that contain unpaired electrons = extremely reactive = want to grab electron from somewhere else = propagating reaction
How are superoxide radicals produced
In ETC e- can accidently escape chain and react with dissolved O2 = superoxide
What is a reactive oxygen species (ROS)
Group of oxygen related compounds that have free radicals = superoxide, hydroxyl radical
What is a reactive nitrogen species (RNS)
Group of nitrogen related compounds that have free radicals = nitric oxide
What is the most damaging free radical?
Hydroxyl radical = reacts with anything
What are the 2 main types of DNA damage by ROS?
Reacting with base = mispairing/mutation.
Reacting with sugar = strand break
How do ROS damage proteins?
Backbone damage = fragmentation = degradation.
Sidechain damage = structure change = function change = loss/gain.
Inappropriate disulphide bond formation if ROS take e- from cysteines
How do ROS damage lipids?
Damage the cell membrane = propagated chain reaction = membrane integrity fails
What are the sources of biological oxidants?
Endogenous = ETC, nitic oxide synthesis, NADPH oxidases.
Exogenous = radiation, drugs, toxins
What is the respiratory burst?
Phagocytic cells prod superoxide = rapid release = destroy invading bacteria
What happens when the respiratory burst is dysfunctional?
Chronic granulomatous disease = defect in NADPH oxidase = can’t form ROS to kill bacteria = more prone to infections
Outline defences against reactive oxygen species
Superoxide dismutase (SOD) = converts superoxide to H2O2 + O2 THEN catalase converts H2O2 to water + oxygen.
Free radical scavengers = vit E = donate H atom to free radicals, nonenzymatic, Vit C regenerates vit E
Glutathione
How does glutathione protect the cell against oxidative damage?
Glutathione = donates e- to free radical (requires glutathione peroxidase),
regeneration of glutathione requires glutathione reductase (needs NADPH from the pentose phosphate pathway)
Explain the role of oxidative stress in galactosaemia
Galactosaemia = def in any of the 3 key enzymes
pathway converts = galactose (via NADPH –> NADP+) to galactitol
= using up NADPH which is required to regenerate glutathione which protects cells from free radicals
= prone to ROS damage = crystalline denatured = cataract
Explain the role of oxidative stress in the formation of Heinz bodies
G6PDH def = low NADPH regeneration = low glutathione regenerated = low protection from free radicals = protein damage = aggregates of cross-lined Hb = Heinz bodies
How does a paracetamol overdose cause toxicity to the liver?
Overdose = prod of NAPQI toxic metabolite = oxidative damage to liver.
Liver try to combat by reacting NAPQI with glutathione = depletes stores = damage elsewhere
What drug should be given after a paracetamol overdose and why?
Acetylcysteine = replenishes glutathione levels
With a def of galactokinase what substance would build up?
Galactitol = build up in osmotic pressure = cataract
Does aldehyde dehydrogenase have a low or high Km for acetaldehyde?
Low Km
Disulphide bone in a protein can form between 2 residues of which AA?
Cysteine
Which enzyme converts superoxide to H2O2 and oxygen?
Superoxide dismutase (SOD)
Which enzyme converts H2O2 to water and oxygen?
Catalase
Which fat soluble vit acts as a free radical scavenger?
E
What toxic metabolite accumulates in the liver a during paracetamol overdose?
NAPQI
What is the role of G6PDH?
To convert NADP back to NADPH
What is the role of NADPH?
Reduction of oxidised glutathione = to protect cells
What happens in G6PDH def?
= limits amount of NADPH prod = reduced amount of glutathione regenerated by NADPH = less protection from oxidative stress
What is the clinical sign of G6PDH?
Heinz bodies
How does NAPQI cause liver damage?
Damage to protein/DNA
Oxidative degradation of lipids
