Session 1: Alcohol Metabolism and Oxidative Stress Flashcards
• Describe how alcohol is metabolised and explain how alcohol can cause liver damage. • Explain the mechanism of action of Disulfiram • Describe the production of superoxide radicals • Discuss other reactive oxygen (ROS) and reactive nitrogen (RNS) species. • Outline defences against reactive oxygen species • Explain the role of oxidative stress in disease state examples
Where is alcohol mainly metabolised?
In the liver. 90%
Where does the remaining alcohol go?
It is excreted passively in urine and on breath.
What is the recommended limit of alcohol intake per week?
14 units/week spread over at least 3 days for both men and women.
What is a unit of alcohol?
8 g or 10 ml of pure alcohol
Describe the rate of elimination of alcohol.
It occurs at a constant rate. Around 7 gram per hour.
Smaller amount of alcohol can also be oxidised by a number of enzymes. Which and where?
Cytochrome P450 2E1 enzyme (CYP2E1)
Catalase in the brain
Outline the metabolism of alcohol.
Happens mainly in liver.
Alcohol -> Acetaldehyde -> Acetate
What enzyme converts alcohol to acetaldehyde?
Alcohol dehydrogenase
What enzyme converts acetaldehyde to acetate?
Aldehyde dehydrogenase
What are the products of alcohol metabolism?
Acetate and two NADH from NAD+.
Briefly outline acetaldehyde.
It is a toxic metabolite which in a build up of it causes hangover.
Briefly outline acetate.
It can react with coenzyme A in order to form acetyl-CoA. This can in its turn be used in TCA cycle or go on to fatty acid synthesis.
How is acetaldehyde toxic?
In excessive amounts it can accumulate in the liver and cause liver damage.
What are the metabolic responses to chronic alcohol consumptions?
There will be a decrease in the NAD+/NADH ratio as NAD+ is used up.
There will be an increase in acetyl-CoA.
What are the consequences of a decreased NAD+/NADH ratio?
- Inadequate NAD+ for conversion of lactate to pyruvate
- Inadequate NAD+ for glycerol metabolism
- Inadequate NAD+ for fatty acid oxidation
What is a consequence of inadequate NAD+ for conversion of lactate to pyruvate?
Lactate will build up in the blood. This can cause lactic acidosis.
Apart from lactic acidosis, what else can lactate accumulation cause?
A reduction in the kidney’s ability to excrete uric acid. This causes an accumulation of urate crystals in tissues producing gout.
What is a consequence of inadequate NAD+ for glycerol metabolism?
A deficit in gluconeogenesis which can lead to hypoglycaemia.
What is a consequence of inadequate NAD+ for fatty acid oxidation?
An increased synthesis of Triacylglycerol.
What is a consequence of increased acetyl-CoA?
Increased synthesis of fatty acids and ketone bodies.
What is a consequence of increased synthesis of fatty acids and ketone bodies?
Increased synthesis of triacylglycerol.
What is a consequence of increased synthesis of triacylglycerol?
A fatty liver.
Give an example of a drug used to treat alcohol dependence.
Disulfiram
Explain the mechanism of Disulfiram.
Disulfiram acts on aldehyde dehydrogenase. This means that there will be an accumulation of acetaldehyde. It prevents the conversion to acetate.
Acetylaldehyde is toxic in its accumulation in the liver. How can then Disulfiram be a drug used to treat chronic alcohol dependence.
Acetaldehyde will accumulate yes, however it can’t be turned into acetate which means the patient will get a much worse hangover. This is not a biological approach of treating CAD but rather a psychological. A much worse hangover might give you an incentive to stop as every time you drink you feel sick.
What are free radicals?
An atom or molecule that contains one or more unpaired electrons. This means that they want another electron and will get it from other atoms, molecules or ions.
This reaction of a radical with a molecule will typically generate a second radical and thereby propagating damage.
What are reactive oxygen species?
ROS are either free radicals or non free radicals with oxygen.
Give examples of free radical and non-free radical with oxygen that are ROS.
Free radical: Hydroxyl radical OH• Superoxide O2•- Nonfree radical: Hydrogen peroxide H2O2 (oxidant)
What are reactive nitrogen species? Give examples.
Free radicals or oxidants that have nitrogen in them.
Nitric oxide NO• (free radical)
Peroxynitrite ONOO- (powerful oxidant)
What do ROS and RNS do to cells?
They can damage nucleic acids, proteins and lipids.
What are the sources of ROS and RNS?
They can be both external and internal sources.
How do you defend from ROS and RNS?
By using antioxidants which reach with the free radicals or oxidants.
Outline the reactive oxygen species.
Oxygen is a biradical mean it has 2 unpaired electrons in different orbitals. It can gain an electron to form a free radical called Superoxide (O2•-).
Superoxide can gain 2 protons and an electron to form the oxidant hydrogen peroxide (H2O2)
Hydrogen peroxide can react with iron (Fe2+) in order to produce free radicals.
Hydrogen peroxide can gain an electron and a protein in order to form water (H2O) and a hydroxyl radical OH• which is the most reactive and damaging free radical as it reacts with anything. As this then gains an electron and a proton it will form water.
Outline the reactive nitrogen species.
Nitric oxide (NO•) reacts with superoxide (O2•-) to form peroxynitrite (ONOO-). Peroxynitrite is not itself a free radical but a powerful oxidant that can damage cells.
How can ROS damage DNA? What main types of damage are there?
ROS can react with a base which can lead to misfiring and mutation.
ROS can react with a sugar (deoxyribose or ribose) which can cause strand break and mutation on repair.
This can lead to cancer.
How can we measure oxidative damage?
By the amount of 8-oxo-dG present in cells. 8-oxo-dG is an oxidised Deoxyguanosine.