Lecture 1 (Alcohol metabolism & Oxidative stress) Flashcards
(44 cards)
Does alcohol have a higher energy content than carbohydrates?
Yes, higher than carbohydrates and proteins but lower than fats
Where is alcohol metabolised?
Liver.
The remainder will be excreted passively in urine and on breath
How is alcohol (ethanol) metabolised?
Alcohol is oxidised (loss of hydrogen) to actealdehyde by alcohol dehydrogenase.
Then acetaldehyde is oxidised (loss of hydrogen) to acetate by aldehyde dehydrogenase.
Acetate is converted to acetyl-coA which enters the TCA(Krebbs)/fatty acid synthesis.
Small amounts of alcohol are oxidised by the cytochrome P450 enzyme (CYP2E1) or by catalase in the brain
What is the recommended limit of alcohol?
14 units, spread across the week (same for men and women)
How many grams of ethanol does 1 unit of alcohol contain and how quickly is it eliminated?
8 grams of ethanol per unit
Eliminated via 0 order kinetics at roughly 7 grams per hour
What order does the metabolism of alcohol present?
Zero order kinetics
Rate of elimination is constant (you don’t get faster elimination if you have a higher concentration of ethanol in your blood)
What are the roles of alcohol dehydrogenase and aldehyde dehydrogenase?
Alcohol dehydrogenase oxidises alcohol (ethanol) to acetaldehyde.
Aldehyde dehydrogenase oxidises acetaldehyde to acetate
Therefore they both reduce NAD+ to NADH.
What is the effect of the accumulation of acetaldehyde in the liver?
Toxic, so can cause liver cirrhosis.
Contributes to the feeling of hangovers coupled with the dehydration from ethanol (as it inhibits secretion of ADH from the posterior pituitary)
What are the consequences of obtaining energy from ethanol?
Uses up NAD+
- lactate can’t be converted to pyruvate via lactate dehydrogenase (enzyme requires NAD+ > NADH), therefore lactate accumulates in blood causing LACTIC ACIDOSIS
- lactate and uric acid use the same transporter in the kidney, with excess lactate, the ability to excrete uric acid is reduced therefore urate crystals accumulate in tissues = GOUT
- increased supply of acetyl-coA causing increase in synthesis of fatty acids/ketone bodies (come from fatty acids): FATTY LIVER
- limits the metabolism of glycerol, limiting gluconeogenesis: HYPOGLYCAEMIA
- limits fatty acid oxidation (metabolism of fatty acids to acetyl-coA units-catabolic), causing an increase in triacylglycerol syntheis causing accumulation
How does the liver export fat?
Fat is packaged into lipoprotein particles.
(protein synthesis is required to make these, so if this is limite then fat will accumulate in the liver = FATTY LIVER
What is gout?
Form of arthritis caused by excess uric acid in the bloodstream causing formation of uric acid crystals in joints (most commonly affects big toe)
What damage can consumption of alcohol lead to?
- fatty liver
- alcoholic hepatitis (inflammation of liver)
- alcoholic cirrhosis
How is acetaldehyde toxicity handled?
Aldehyde dehydrogenase has a low Km for acetaldehyde, so it acts quickly keeping levels of acetaldehyde low.
(low Km = high substrate affinity)
What drug is used to treat alcohol dependence?
Disulfiram. It is an inhibitor of aldehyde dehydrogenase. Causing an accumulation of acetaldehyde making you feel sick. The patient then associates drinking with feeling sick, making them stop.
Why is oxidative stress important?
It contributes to many disease states (MS, COPD, cancer, cardiovascular disease)
What is oxidative stress?
An imbalance between our defence mechanisms and stress placed on cells from free radicals
What is a free radical and what does it cause?
A free radical is an atom/molecule that contains one or more upaired electrons and it leads to oxidative stress. It pinches an electron off another molecule causing damage to the cell. (denoted by subscript dot)
What is an ROS?
Reactive oxygen species. (also used to describe reactive nitrogen species)
Give some examples of ROS’s:
-Oxygen is a biradical (has 2 unpaired electron) which are in different orbitals, so this molecule is quite stable
-if oxygen gains another electron from another species it forms SUPEROXIDE
-superoxide can then take 2 hydrogens and 1 electron to form HYDROGEN PEROXIDE (not a free radical but is toxic to cells)
-hydrogen peroxide then gains another electron to form WATER and a HYDROXYL RADICAL (most damaging as can pinch and electron off anything)
(hydroxyl radical can form water with the gain of an electron and proton)
Why is hydrogen peroxide dangerous?
Hydrogen peroxide can react with Fe2+ to produce free radicals via The Fenton Reaction (converts hydrogen peroxide to hydroxyl radical)
Give an example of a Reactive Nitrogen Species:
Nitric oxide (NO) can react with superoxide to form PEROXYNITRILE, which is a powerful oxidant.
How can ROS damage DNA?
Removal of an electron from a base/sugar of DNA.
-modification of a base can lead to MISPAIRING and mutation
-modification of a sugar can cause a STRAND BREAK and mutation on repair
Failure to repair leads to accumulation of mutations which can lead to cancer
What is 8-oxo-dG?
When deoxyguanosine has been damaged by ROS it produces 8-oxo-dG.
A measurement of the amount of this can give indication of the amount of oxidative stress the patient is experiencing as it accumulates in DNA
How can ROS damage proteins?
Reaction with backbone:
-fragmentation leading to protein degredation
Reaction with side chains forming:
-dimers
-hydroxylated adducts
-carbonyls
-disulphide bonds between cysteine residues which are unnatural causing a change in protein structure
This can lead to loss/gain of function of proteins, the loss of function proteins will be degraded.
