Alcohol Metabolism And Oxidative Stress Flashcards
(33 cards)
Where is the majority of alcohol metabolised? How is the remainder excreted?
> 90% of alcohol is metabolised In the liver
Remainder excreted passively through urine and on breath
What enzymes can oxidise alcohol?
Alcohol dehydrogenase (to acetaldehyde)
Aldehyde dehydrogenase (to acetate)
Small amounts:
CYP2E1 - (Cytochrome P450 2E1 Enzyme)
Catalase - in the brain
What is the recommended limit for alcohol?
14 units
Spread over at least 3 days
BOTH men and women
What is the rate of elimination of alcohol?
~7g per hour
Half pint of normal strength beer
Small glass of wine / hour
State the pathway of alcohol metabolism
1) Alcohol is oxidised from ethanol to acetaldehyde by alcohol dehydrogenase, NAD+ goes to NADH
2) acetaldehyde is oxidised to acetate by aldehyde dehydrogenase, NAD+ is again reduced to NADH
What substance is responsible for the symptoms of a ‘hangover’?
The accumulation of acetaldehyde, which is a toxic metabolite causes the typical symptoms of a hangover
What is the fate of the acetate product produced from alcohol metabolism?
It is conjugated to co-enzyme A to produce acetyl-coA and metabolised in TCA cycle or use for fatty acid synthesis
How does the consumption of alcohol cause damage to the liver?
Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde accumulation to cause liver damage
Usually kept to a minimum by acetaldehyde dehydrogenase which has low Km for acetaldehyde
Excess NADH and Acetyl-coA lead to changes in liver metabolism
Fatty liver
Alcoholic hepatitis
Alcoholic cirrhosis
What is cirrhosis?
Cirrhosis is the severe scarring of the liver and poor liver function seen at the terminal stages of chronic liver disease. The scarring is most often caused by long-term exposure to toxins such as alcohol or viral infections.
What is the overall chronic alcohol consumption outcomes?
Reduce NAD+/NADH Ratio (i.e reduced NAD+)
Increased Acetyl-coA
what are the effects of increased NADH levels?
inadequate NAD+ for conversion of lactate to pyruvate
-lactate accumulates in blood leading to lactic acidosis
decreases kidneys ability to excrete uric acid
-urate crystals accumulate in tissues producing gout
Inadequate NAD+ for glycerol metabolism
- lactate accumulation effects also
deficit in gluconeogenesis
-leads to hypoglycaemia
inadequate NAD+ for fatty acid oxidation
-increased synthesis of triacylglycerol
what are the effects of increased acetyl-coA?
Increased acetyl-coA -increased synthesis of fatty acids and ketone bodies -Increased synthesis of triacylglycerol And lower lipoprotein synthesis -leads to a fatty liver
what is used for treatment of alcohol dependance?
Disulfiram
What is the mechanism of action of Disulfiram?
Disulfiram can be used as a adjunct in the treatment of chronic alcohol dependance
inhibitor of aldehyde dehydrogenase
if the patient drinks alcohol acetaldehyde will accumulate and cause the symptoms of a ‘hangover’
what is a free radical?
An atom or molecule that contains one or more unpaired electrons and is capable of independent (‘free’) existence
How are super oxide molecules produced?
Molecular oxygen is a biradical. it has 2 unpaired electrons in different orbitals.
Super oxide : O2 . - is produced by adding a electron to molecular oxygen
How can the hydroxyl radical be produced from oxygen? why is this damaging?
once converted to superoxide the oxygen molecule can gain 2H+ and a e- to produce Hydrogen peroxide (H2O2)
When combined with H+ and e- this produces the Hydroxyl radical
This is the most reactive and damaging free radical and will react with almost anything.
(Hydroxyl added to H+ e- creates water)
how can superoxide produce peroxynitrite?
superoxide (O2. -) can react with Nitric oxide (NO.) to produce peroxynitrite (ONOO-)
this is not a free radical in itself but is a powerful oxidant that can damage cells
How can ROS’ damage DNA?
1) ROS reacts with base - modified base can lead to mispairing and mutation
2) ROS reacts with sugar - can cause strand break and mutation on repair
DNA and/or failure to repair can lead to mutation which can lead to cancer.
What molecule can be used as an indication of the amount of oxidative damage?
8-oxo-dG
deoxyguanosine —-ROS—-> 8-oxo-2’-deoxyguanosine
How can ROS’ damage proteins?
1) Reacting with carbons in backbone
- leads to fragmentation
- protein degradation
2) Reacting with side chain
- Modified amino acid (e.g carbonyls, disulphide bonds)
- changes in protein structure
- Loss of function of protein or gain of function
- Protein degradation
What affect can ROS’ have on disulphide bonds?
- disulphide bonds play an important role in folding and stability of some proteins
- formed between thiol groups of cysteine residues
- Inappropriate disulphide bonds can form if ROS takes electrons from cysteines causing misfolding, crosslinking and disruption of function (e.g enzyme)
How can ROS’ disrupt lipid bilayer stability?
- Free radical (e.g OH . ) can extract H from polyunsaturated fatty acid in lipid bilayer
- Lipid radical formed can react with oxygen to form lipid peroxyl radical
- chain reaction as lipid peroxyl radical extracts H from nearby fatty acids
Hydrophobic environment of bilayer disrupted and membrane integrity falls
give 3 examples of endogenous and exogenous sources of biological oxidants
ENDOGENOUS
- ETC
- Nitric oxide synthases
- NADPH Oxidases
EXOGENOUS
- radiation
- pollutants
- drugs (primaquine - anti malarial)
- Toxins (paraquat - herbicide)
