Where does alcohol metabolism occur?
- >90% alcohol is metabolised by liver
- Remainder is excreted passively in urine and on breath
What are the recommended limits for alcohol consumption?
14 units/week spread over at least 3 days for both men & women
Briefly describe the pathway involved in alcohol metabolism
What happens when acetaldehyde accumulates?
- Acetaldehyde is a toxic metabolite
- Accumulation causes a “Hangover”
What happens to the acetate produced in alcohol metabolism?
- Acetate is conjugated to coenzyme A to form acetyl-CoA
- Acetyl-CoA is metabolised in TCA cycle / utilised for fatty acid synthesis
How is acetaldehyde toxicity controlled?
Acetaldehyde toxicity normally kept to a minimum by aldehyde dehydrogenase (low Km for acetaldehyde)
How does liver damage occur?
Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde accumulation to cause liver damage
Identify three forms of liver damage resulting from prolonged and excessive alcohol consumption
- “Fatty liver”
- Alcoholic hepatitis
- Alcoholic cirrhosis
Indicate how liver damage can lead to changes in liver metabolism
- Excess NADH (decreased NAD:NADH)
- Excess Acetyl-CoA
What are the consequences of liver damage due to prolonged and excessive alcohol consumption?
- Lactic acidosis
- Fatty liver
Illustrate how excess NADH and Acetyl-CoA resulting from alcoholic liver damage can lead to the following consequences:
- Lactic acidosis
- Fatty liver
Which drug can be used to treat chronic alcohol dependence?
Explain how Disulfiram treats chronic alcohol dependence
- Disulfiram is an inhibitor of aldehyde dehydrogenase
- If patient drinks alcohol acetaldehyde will accumulate causing symptoms of a ‘hangover’
Cellular damage caused by ROS & RNS is a significant component in a wide range of disease states.
What is a free radical?
A free radical is an atom or molecule that contains 1/more unpaired electrons and is capable of independent existence e.g. OH•
Why are free radicals so damaging?
- Free radicals are usually very reactive and tend to acquire electrons from other atoms, molecules or ions
- Reaction of a radical with a molecule typically generates a second radical thereby propagating damage
What are the two types of free radicals found in the body?
- Reactive Oxygen Species
- Reactive Nitrogen Species
Describe the pathway involved in the formation of reactive oxygen species
Explain how reactive nitrogen species are formed
O2•- + NO• → ONOO-
- Superoxide can react with nitric oxide to produce peroxynitrite
- Peroxynitrite is not a free radical, but is a powerful oxidant which damages cells
Which three structures can ROS damage?
Outline the two ways in which ROS can damage DNA
- ROS reacts with base – modified base can lead to mispairing and mutation
- ROS reacts with sugar (ribose or deoxyribose) – causing strand break and mutation
What are the possible consequences of ROS damage to DNA?
Outline, in detail, the two ways that ROS can damage proteins and the consequences of this
Disulphide bonds are formed between thiol groups of cysteine residues and play an important role in folding and stability of some proteins.
What happens when ROS interfere with these bonds?
Inappropriate disulphide bond formation can occur if ROS takes electrons from cysteines causing misfolding, crosslinking and disruption of function e.g. enzyme
Which process in triggered when ROS react with lipids?
In three steps, describe how lipid peroxidation occurs
⇒ Free radical extracts H+ from a polyunsaturated fatty acid in membrane lipid
⇒ Lipid radical forms & reacts with O2 to form a lipid peroxyl radical
⇒ Chain reaction formed as lipid peroxyl radical extracts hydrogen from nearby fatty acid
What are the consequences of lipid peroxidation?
Hydrophobic environment of bilayer disrupted and membrane integrity fails
Identify three endogenous sources of biological oxidants
- Electron transport chain
- Nitric oxide synthases
- NADPH oxidases
Identify four exogenous sources of biological oxidants
Explain how the ETC can be an endogenous source of ROS
- Electrons pass through ETC and reduce oxygen to form H2O at Complex IV
- Occasionally electrons can accidently escape chain and react with dissolved O2 to form superoxide