MEH - Alcohol Metabolism And Oxidative Stress Flashcards Preview

CJ: UoL Medicine Semester Two (ESA2) > MEH - Alcohol Metabolism And Oxidative Stress > Flashcards

Flashcards in MEH - Alcohol Metabolism And Oxidative Stress Deck (46):

Where is most (over 90%) alcohol metabolised?

In the liver, remainder is excreted passively in urine and on breath


What is the UK recommendation for alcohol consumption?

14 units/week spread over at least 3 days


How are very small amounts of alcohol metabolised outside the liver?

Using the cytochrome P450 2E1 enzyme, or by catalase in the brain


How fast is alcohol eliminated?

Around 7g an hour


Outline the main pathway of alcohol metabolism

- Ethanol is converted to acetaldehyde by alcohol dehydrogenase (makes NADH)
- acetaldehyde is converted to acetate by aldehyde dehydrogenase (makes NADH)
- acetate is conjugated to coenzyme A to form acetyl CoA, it is then used in TCA cycle or fatty acid synthesis


Which part of the alcohol metabolism sequence is responsible for the 'hangover'?

Acetaldehyde, as it is a toxic metabolite


Does aldehyde dehydrogenase have a high or low Km?

Low meaning it can keep acetaldehyde conc. low


Give some liver conditions that can occur as a result of over consumption of alcohol

- 'fatty liver'
- alcoholic hepatitis
- alcoholic cirrhosis


How does excess alcohol oxidation lead to fatty liver?

- Increased acetyl-coA formation leads to increased synthesis of fatty acids and ketone bodies
- increased synthesis of triacylglycerol
- inadequate NAD+ for fatty acid oxidation and lower lipoprotein synthesis all lead to fatty liver


How does overconsumption of alcohol lead to lactic acidosis?

- decrease in NAD+/NADH ratio
- inadequate NAD+ for conversion of lactate to pyruvate
- lactate accumulates in blood
- lactic acidosis occurs


How does overconsumption of alcohol lead to urate crystals accumulating in tissues and forming gout?

- decrease in NAD+/NADH ratio
- inadequate NAD+ for conversion of lactate to pyruvate
- lactate accumulates in blood
- kidney's ability to excrete uric acid reduced
- urate crystals accumulate in tissues producing gout


How does excessive alcohol consumption lead to hypoglycaemia?

- decrease in NAD+/NADH ratio
- inadequate NAD+ for glycerol metabolism
- deficit in gluconeogenesis
- hypoglycaemia occurs


How can disulfiram be used for the treatment of alcohol dependence?

It inhibits aldehyde dehydrogenase, so if a patient drinks alcohol they will get symptoms of an extremely bad hangover


What is a free radical?

An atom/molecule that contains one or more unpaired electrons and is capable of independent existence. They are usually extremely reactive and tend to acquire electrons from other atoms/molecules/ions, which generates a second radical propagating damage.


Give some examples of reactive oxygen species

Oxygen, superoxide, hydrogen peroxide, hydroxyl radical


Which is the most damaging reactive oxygen species?

Hydroxyl radical


Give some examples of reactive nitrogen species

Nitric oxide and peroxynitrite


What are the two types of ROS damage to DNA?

- ROS reacts with base (modified base can lead to mispairing and mutation)
- ROS reacts with sugar (can cause strand break and mutation on repair)


How can the amount of oxidative damage which has occurred to DNA be measured?

Measure amount of 8-oxo-dG present in cells


Give some examples of ways that ROS can damage proteins

Modified side chains eg:
- carbonyls
- hydroxylated adducts
- ring opened species
- dimers
- disulphide bonds

These lead to a change in protein structure which causes loss/gain of function and may lead to protein degradation


How do disulphide bonds form?

Formed between thiol groups of cysteine residues


How can ROS affect disulphide bond formation?

Can cause inappropriate bond formation if ROS takes electrons from cysteines causing misfolding, cross linking and disruption of function


How do ROS damage lipids?

- free radical extracts hydrogen atom from polyunsaturated fatty acid in membrane lipid
- lipid radical formed which can react with oxygen to form lipid peroxyl radical
- chain reaction as lipid peroxyl radical extracts hydrogen from nearby fatty acid
- hydrophobic bilayer disrupted and membrane integrity fails


Give some endogenous sources of biological oxidants

- electron transport chain
- peroxidases
- nitric oxide synthases
- lipooxygenases
- NADPH oxidases
- xanthine oxidase
- monoamine oxidase


Give some exogenous sources of biological oxidants

- radiation (cosmic rays, UV light, X-rays)
- pollutants
- drugs (eg. primaquine which is an anti-malarial)
- toxins (eg. Paraguat which is a herbicide)


How does the electron transport chain form ROS?

Occasionally, electrons can accidentally escape the chain and react with dissolved O2 to form superoxide


What are the three types of nitric oxide synthase?

- iNOS (inducible nitric oxide, produces high NO conc in phagocytes for direct toxic effect)
- eNOS (endothelial nitric oxide synthase for signalling)
- nNOS (neuronal nitric oxide synthase for signalling)


How is nitric oxide produced?

Formed when nitric oxide synthase converts arginine to citrulline and NO


What is nitric oxide used for?

- signalling molecule
- vasodilation
- neurotransmission
- S-nitrosylation

It is toxic at a high level


What is a 'respiratory burst'?

Rapid release of superoxide and H2O2 from phagocytic cells. ROS and peroxynitrite destroy invading bacteria


What is chronic granulomatous disease?

Genetic defect in NADPH oxidase complex which causes enhanced susceptibility to bacterial infections. Symptoms include atypical infections, pneumonia, abscesses, impetigo and cellulitis


How does superoxide dismutase defend the cell against oxidative damage?

Converts superoxide to H2O2 and oxygen


How does catalase protect cells from ROS?

Converts H2O2 to water and oxygen.


What is glutathione?

A tripeptide synthesised by the body to protect against oxidative damage.


How does glutathione work?

The thiol group of the reduced form (GSH) donates an e- to ROS, then reacts with another GSH to form a disulphide bond (GSSG). Glutathione peroxidase allows this - it requires selenium.

GSSG reduced back to GSH by glutathione reductase which catalyses transfer of electrons from NADPH to disulphide bond. NADPH is essential.


Why is the penthouse phosphate pathway crucial for protection against oxidative damage?

Provides NADPH which is required for glutathione to work


Why are vitamin C and vitamin E important for protection against ROS?

- vitamin E is a lipid soluble antioxidant which protects against lipid peroxidation
- vitamin C is a water soluble antioxidant which regenerates the reduced form of vitamin E


How do free radical scavengers protect against ROS?

They reduce damage by donating a hydrogen atom to free radicals in an non-enzymatic reaction


Give some examples of free radical scavengers

- vitamin E
- vitamin C
- carotenoids
- flavonoids
- uric acids
- melatonin


How is galactosaemia caused?

Deficiency in either galactokinase, UDP-galactose epimerase or uridyl transferase leads to inability to metabolise galactose correctly


Give some symptoms of galactosaemia

- hepatomegaly and cirrhosis
- renal failure
- vomiting
- seizure and brain damage
- cataracts
- hypoglycaemia


How can glucose-6P dehydrogenase deficiency lead to less protection form ROS?

Decreased G6PDH activity limits amount of NADPH, meaning lower GSH levels and less protection


What are Heinz bodies?

Dark staining within red blood cells resulting from precipitated haemoglobin. They bind to the cell membrane, altering the rigidity of the cell and causing increased mechanical stress when cells squeeze through small capillaries. They are a clinical sign of G6PDH deficiency


How is paracetamol normally metabolised?

Usually removed by liver by conjugation with glucuronide or sulphate


What happens if a high level of paracetamol is consumed?

- A toxic metabolite called NAPQI is formed. It causes oxidative damage to the liver cells (lipid peroxidation, damage to proteins, damage to DNA).
- the liver tries to counter this by reacting with glutathione, but it starts to run out and leads to more oxidative damage


How should paracetamol overdose be treated?

Administer acetylcysteine, which replenishes glutathione levels and allows toxic NAPQI to be removed from the body

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