S3) Alcohol Metabolism & Oxidative Stress Flashcards
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
- Hypoglycaemia
- Gout
Illustrate how excess NADH and Acetyl-CoA resulting from alcoholic liver damage can lead to the following consequences:
- Lactic acidosis
- Gout
- Hypoglycaemia
- Fatty liver
Which drug can be used to treat chronic alcohol dependence?
Disulfiram
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.
Identify some
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?
- DNA
- Proteins
- Lipids
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?
Lipid peroxidation
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
- Radiation
- Pollutants
- Drugs
- Toxins
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
Explain the pathway in which nitric oxide synthase acts as an endogenous source of ROS
Arginine → Citrulline + NO•
- Nitric oxide synthase catalyses this reaction
- NO• is toxic in high levels
What are the three types nitric oxide synthase?
- iNOS: inducible nitric oxide synthase (direct toxic effect in phagocytes)
- eNOS: endothelial nitric oxide synthase (signalling)
- nNOS: neuronal nitric oxide sytnthase (signalling)
Illustrate how biological oxidants are part of antimicrobial defence system
- Rapid release of superoxide & H2O2 from phagocytic cells
- ROS and peroxynitrite destroy invading bacteria
What is chronic granulomatous disease?
Chronic granulomatous disease is a condition caused by a genetic defect in NADPH oxidase complex leading to an enhanced susceptibility to bacterial infections e.g. pneumonia, cellulitis, impetigo
Identify three cellular defences against biological oxidants
- Superoxide dismutase
- Catalase
- Glutathione
Explain the action of superoxide dismustase as a cellular defence
- Converts superoxide to hydrogen peroxide and oxygen
- Primary defence as superoxide is strong initiator of chain reactions
Explain the action of catalase as a cellular defence
- Converts hydrogen peroxide to water and oxygen
- Important in immune cells to protect against oxidative burst
What is glutathione?
Glutathione is a tripeptide synthesised by body to protects against oxidative damage
Explain the action of glutathione as a cellular defence
⇒ The thiol group of Cys donates e− to ROS
⇒ GSH then reacts with another GSH to form a disulphide (GSSG)
⇒ GSSG is reduced back to GSH by glutathione reductase which catalyses the transfer of electrons from NADPH to disulphide bond
Identify the two requirements necessary for the action of glutathione
- Glutathione peroxidase requires selenium
- NADPH comes from the pentose phosphate pathway
Which vitamins act as free radical scavengers?
- Vitamin C
- Vitamin E
How do free radical scavengers act as cellular defences against biological oxidants?
Free radical scavengers reduce free radical damage by donating hydrogen atom (and its electron) to free radicals in a nonenzymatic reaction
Explain and illustrate how Vitamin C and E act as free radical scavengers
- Vitamin E: lipid soluble antioxidant important for protection against lipid peroxidation
- Vitamin C: water soluble antioxidant important in regenerating the reduced form of Vitamin E
Identify 5 symptoms of galactosaemia
- Hepatomegaly & cirrhosis
- Renal failure
- Vomiting
- Seizure & brain damage
- Cataracts
In galactosaemia, the accumulation of galactose can lead to the formation of cataracts.
In four steps, describe how this occurs
⇒ Increased activity of aldose reductase consumes excess NADPH
⇒ Compromised defences against ROS damage
⇒ Crystallin protein in lens of eye denatured (+ osmotic pressure)
⇒ Cataracts form
In 5 steps, explain the consequences of GSPDH deficiency
⇒ Decreased G6PDH activity limits amount of NADPH
⇒ Less NADPH available for reduction of GSSG back to GSH
⇒ Lower GSH = less protection against oxidative stress
⇒ Lipid peroxidation & protein damage
⇒ Haemolysis
What are heinz bodies?
- Heinz bodies are aggregates of cross-linked haemoglobin
- The precipitated haemoglobin stains dark within RBCs
What are the effects of heinz bodies?
- Bind to cell membrane altering rigidity
- Increased mechanical stress when cells squeeze through small capillaries
- Spleen removes bound Heinz bodies resulting in “blister cells”
Describe paracetamol metabolism in terms of the following:
- Normal conjugation
- Toxic accumulations
- Treatment
- Oxidative damage
