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
