1.1 Alcohol metabolism and oxidative stress Flashcards
Where is alcohol removed from the body?
Metabolised by the liver
Catabolised by enzyme in the brain
Remainder excreted passively in urine and on breath
How is alcohol metabolised?
In the liver
Alcohol is oxidised by alcohol dehydrogenase (using NAD+ to NADH) into acetaladehyde
Then, acetaldehyde is converted into acetate using aldehyde dehydrogenase (and another NAD+ to NADH)
What causes a hangover?
A build up of acetaldehyde - its a toxic metabolite
What can acetate be used for?
Can form acetyl- CoA for TCA cycle or fatty acid synthesis
What’s the rate of alcohol metabolism? And what are the recommended units?
One unit = 8g
Eliminate alcohol at rate of 7g an hour
Can find one unit in half a pint of beer or a small glass of wine
Recommended units = 14 a week spread over 3 days
What can happen in cases of excess alcohol consumption?
Build up of acetaldehyde, not enough aldehyde dehydrogenase to convert it to acetate so get
- liver cirrhosis
- alcohol hepatitis
- ‘fatty liver’
Also, excess NADH and acetyl CoA production lead to changes in liver metabolism.
How can you get a ‘fatty liver?’
- Increased acetyl co A
- increased synthesis of fatty acid and ketone bodies
- increased synthesis of triacylglycerol
(And low lipoprotein synthesis)
= FATTY liver
Also, less NAD+ = cant do fatty acid oxidation = more triglycerides form
How can you get lactic acidosis?
- decrease in NAD+/NADH ratio
- cant convert lactate to pyruvate as not enough NAD+
- lactate accumulates in blood
= ACIDOSIS
How can alcoholism cause gout?
- Lower NAD/NADH ratio
- not enough NAD to convert lactate to pyruvate
- lactate accumulates in blood
- kidneys ability to excrete Uric acid reduced
- urate crystals accumulate = gout
How can alcoholism cause hypoglycaemia?
- decreased NAD/NADH ratio
- inadequate NAD for glycerol metabolism
- deficit in gluconeogenesis
= HYPOGLYCEMIA
What can be used to treat alcohol dependence and how does it work?
- Disulfiram
- inhibits aldehyde dehydrogenase
- so if patient drinks, acetylaldehyde will accumulate = get symptoms of a hangover and feel sick. So, will associate drinking with a negative feeling = gets them off it.
ROS and RNS can cause oxidative stress. When does oxidative stress occur?
When there is an imbalance of oxidants and defences, with more oxidants than our defences can handle
What’s a free radical?
An atom with an unpaired electron.
NB: reaction of a radical with a molecule typically generates a second radical thereby propagating damage
Name a reactive nitrogen species and how it is formed. What can it do?
- Peroxynitrite (ONOO-) is a RNS
- formed from superoxide and nitric oxide
- is a powerful oxidant
How is superoxide formed??
Add an electron to normal oxygen = superoxide free radical
What’s the most damaging and reactive free radical and ROS?
OH* !!!!!!!!!!!!!!
NB: formed from H2O2, which itself is not a free radical but can readily react with things like fe2+ to make free radicals. Gnarly
How can ROS cause cancer?
- reacts with dna
- dna damage
- failure in repair = mutation
- can lead to cancer
How can ROS damage proteins (backbone and side chains)?
Backbone
- fragmentation = protein degradation
Side chains
- modified amino acids and bonds e.g. disulfied bonds in protein structure = change in protein structure
- loss of function = protein degradation
Sometimes can have gain of function.
What are disulfied bonds formed between?
The thiol groups of cysteine residues.
NB: ROS can cause disulfied bonds to form in random places = miss-folding = chaos.
How can ROS damage lipids?
- Free radical (OH*) takes hydrogen from polyunsaturated fatty acid in membrane lipid
- lipid radical formed, can react with oxygen to form lipid peroxyl radical
- hydrophobic environment of bilayer disrupted and membrane integrity falls (I’m yelling timber)
Name 3 endogenous and 3 exogenous sources of biological oxidants.
Endogenous
- electron transport chain (electron escapes and reacts with o2 to form superoxide)
- NADPH oxidises
- nitric oxide syntheses
Exogenous
- radiation
- pollutants
- toxins
What are the effects of NO*?
Signalling molecule
- vasodilation
- neurotransmission
- toxic at high levels
What is respiratory burst?
- rapid release of superoxide and h2o2 from phagocytise cells
- ROS and peroxynitrite destroy invading bacteria
- part of antimicrobial defence system
What is chronic granulomatous disease?
Genetic defect in NADPH oxidase complex = increases susceptibility to bacteria infections such as:
- cellulitis
- abscesses
- pneumonia
- atypical infections
What is the role of superoxide dismutase? (SOD)
- converts superoxide to h202 and oxygen
- is cytosolic, extracellular and mitochondrial
What is the role of catalase?
- converts h202 to water and oxygen
What is glutathione?
- tripeptide synthesised to protect against oxidative damage
- has cysteine group for disulfied bonds to form
- also glutathione peroxidase which facilitates this process converts h202 to h20 = reduces amount of free radicals around
What is the pentose phosphate pathway?
- starts from glucose 6 phosphate
- important source of NADPH for processes e.g detoxification and reducing
- no atp produces, just co2
- produces C5 sugar ribose for things e.g nucleotides and DNA
- rate limiting enzyme is glucose 6 phosphate dehydrogenase
Name two free radical scavengers and how they work.
Vitamin E
- important for protection against lipid peroxidation
- turns lipid radical back into normal lipid
Vitamin c
- regenerates reduced form of vitamin E
How do people get galactosaemia? And then cataracts?
Deficiency in one of three enzymes
- uridyl transferase
- galactokinase
- UDP galactose epimerise
Means that aldosterone reductase will have to work harder to remove galactose and convert galactose (formed from glucose and dietary lactose) into galactitol = increased osmotic pressure in eye = can get cataracts.
NB: increased activity of aldose reductase consumped NADPH = compromised defence against ROS damage - crystalline protein in lens of eye denature = cataracts
What are the consequences of a glucose 6 phosphate dehydrogenase reaction?
- decrease in activity = limits amount of NADPH needed for reduction of glutathione in its oxidised form
- lower reduced glutathione means less protection against oxidative stress
- as a result can get lipid peroxidatio and protein damage, which may present as Heinz bodies (aggregation of cross linked haemoglobin) (haemolysis)
What are Heinz bodies?
- dark staining within red blood cell resulting from precipitated haemoglobin
- bind to cell membrane altering rigidity
- increase mechanical stress when squeezing through small capillaries
- spleen removes them
- clinical sign of G6PDH deficiency
How is paracetamol metabolised?
- at prescribed dosage, is metabolised with sulphate or glucuronide
- high levels taken = toxic metabolism NAPQI is made. Causes oxidative damage to live cells (proteins, DNA and lipid peroxidation)
- also converted to glutathione which tries to fix this but then you get glutathione depletion since its working so hard and cant keep up with NAPQIs effects
- treat with acetyl cysteine to replenish glutathione levels
