Alcohol Metabolism and Oxidative Stress Flashcards
Describe the energy content of alcohol
High energy content (29KJ/g) but not as high as fat.
Where is alcohol metabolised?
>90% by the liver, the remainder is passively excreted in the urine or breath.
What are the stages of alcohol metabolism?
Normal pathway (see image)
Smaller amount of alcohol can be oxidised by CYP2E1 (P450 family member) or by catalase in the brain.
What is acetate converted to?
Acetyl coA to be used in the TCA/Krebs cycle or for fatty acid synthesis.
What is the recommended units of alcohol per week?
14 units over at least 3 days for both men and women.
What is the rate of alcohol metabolism?
One unit of alcohol = 8g
1 unit = half a pint of normal strength beer or a small glass of wine
Eliminated at rate of ~7g per hour following zero order kinetics.
When does liver damage occur?
- Acetaldehyde toxicity is kept minimal by aldehyde dehydrogenase which has a low Km for acetaldehyde.
- Prolonged and excessive alcohol consumption can cause sufficient acetaldehyde accumulation to cause liver damage.
- Excess NADH and acetyl-CoA can lead to changes in liver metabolism
What are the stages of alcohol-related liver disease (ALRD)?
Alcoholic fatty liver disease
- build-up of fats in the liver
- asymptomatic
- reversible
Alcohol hepatitis
- Mallory’s hyaline body, swelling and inflammation
- Symptoms: feeling unwell, hepatomegaly and ascites.
- Reversible
Cirrhosis
- Extensive scarring
- Irreversible
How does alcohol consumption lead to lactic acidosis and urate crystals/gout?
Lactic Acidosis
- Decrease in NAD+/NADH ratio
- Lactate cannot be converted to pyruvate and accumulates in the blood.
- Lactic acidosis lowering blood pH
Urate Crystals
- Linked to accumulation of lactate
- Lactate and uridyl acid hare the same transporter in the kidney
- Kidneys ability to excrete uric acid is reduced
- Urate crystal accumulate in tissues producing gout.
How does alcohol metabolism lead to hypoglycaemia?
- Reduced NAD+/ NADH ratio
- inadequate NAD+ for glycerol metabolism
- deficit in gluconeogenesis
- hypoglycaemia
How does alcohol metabolism lead to fatty liver?
- Decrease in NAD+/NADH ratio
- Insufficient NAD+ for fatty acid oxidation and increased acetyl-CoA
- higher acetyl-CoA causes increase synthesis of fatty acids and ketone bodies
- Higher synthesis of fatty acids and inadequate NAD+ leads to increased synthesis of triacylglycerol causing a fatty liver.
What is disulfiram?
- Treatment for chronic alcohol dependence used alongside other treatment.
- Works as an inhibitor of aldehyde dehydrogenase to accumulate acetaldehyde causing symptoms of a hangover.
- Low compliance as pts won’t take a drug that makes them feel sick.
What is oxidative stress?
When the ratio of free radicals and antioxidants/free radical scavengers have an imbalance to favour free radicals.
What diseases are related to oxidative stress?
- Cardiovascular disease
- Alzheimer’s disease
- Rheumatoid arthritis
- Crohn’s disease
- COPD
- Ischaemia - reperfusion injury
- Cancer
- Pancreatitis
- Parkinson’s disease
- Multiple sclerosis
What are free radicals?
an atom or molecules that contain one or more unpaired electrons to produce highly reactive properties of that species.
Damage is caused by acquiring electrons from surrounding tissue thus producing a second free radical causing propagating damage.
How are superoxide radicals produced?
Electrons occasionally escape the ETC and react with dissolved O2 to form superoxide (O2•-).
What are reactive oxygen species?
- Superoxide (O2•-) - electron added from the ETC to molecular oxygen)
- Hydrogen peroxide (H2O2) - not a free radical but can react with Fe2+ to produce free radicals
- Hydroxyl Radical (OH•) -most damaging free radical
What are the reactive nitrogen species?
- Nitric oxide (NO•)
- Produced by nitric oxide synthase when converting arginine to citrulline
- iNOS: inducible. Produces high [NO•] in phagocytes for toxic effects
- eNOS: endothelial. Produces NO• for signalling
- nNOS: neuronal. Produces NO• for signalling
- At high levels has toxic effects
- At small concentrations used as signalling for
- Vasodilation
- Neurotransmission
- S-nitrosylation
- Produced by nitric oxide synthase when converting arginine to citrulline
- Peroxynitrite (ONOO-) - when nitric oxide and superoxide react. Not a free radical but a powerful oxidant that can damage cells.
What does ROS damage?
DNA
- reacts with a base or a sugar
- damages bases and strands
- causes a mutation that can be oncogenic
Proteins
- reacts with backbone or side chain (cysteine)
- backbone results in protein degradation
- sidechain results in a structural change
- loss of function
- gain of function
- protein degradation
Lipids
- reacts with polyunsaturated fatty acid in membrane lipid
- chain reaction/ propagation disrupts the hydrophobic environment of membrane bilayer failing membrane integrity
How are disulphide bonds disrupted by ROS?
- Disulphide bonds mainly found in secreted proteins or extracellular domains
- ROS removes electrons from thiol groups of cysteine residues
- disulphide bonds form between cysteine residues
- inappropriate disulphide bond formation occurs
- misfolding and cross-linking (tertiary structure)
- disruption of protein function occurs
What are the sources of biological oxidants?
Endogenous
- ETC (main source)
- Peroxidases
- Nitric oxide synthases
- Lipoxygenases
- NADPH oxidases
- Xanthine oxidase
- Monoamine oxidase
Exogenous
- Radiation
- cosmic rays
- UV light
- X-rays
- Pollutants
- Drugs
- primaquine (antimalarial) - G6PD deficinency screen before prescribing
- Toxins
- paraquat (herbicide)
What is respiratory burst?
The rapid release of superoxide and hydrogen peroxide from phagocytic cells (neutrophils and monocytes) to destroy invading bacteria.
- peroxynitrite (from O2•- and NO•) and hypochlorite destroy bacteria as part of the antimicrobial defence system
- NADPH oxidase is a membrane-bound complex of phagocytes that produces the superoxide for the microbial defence
What are chronic granulomatous diseases (CGD) and their aetiology?
Inherited primary immunodeficiency disease (PIDD) caused by genetic defects in NADPH oxidase complex. Individuals have an enhanced susceptibility to bacterial infections:
- Atypical infections
- Pneumonia
- Abscesses
- Impetigo
- Cellulitis
What are the cellular defences against oxidative stress?
Superoxide dismutase (SOD)
- converts superoxide to hydrogen peroxide and oxygen
- primary defence
- 3 isoenzyme
- cytosolic
- extracellular
- mitochondria
Catalase
- converts hydrogen peroxide to water and oxygen
- wide spread enzyme; vital in immune cells to protect against oxidative burst
- decline in hair follicles causes grey hair
Glutathione (GSH and GSSG)
- tripeptide synthesised by the body
- reforms disrupted disulphide bonds using electrons from NADPH from the pentose phosphate pathway
- glutathione reductase requires selenium
Free Radical Scavengers - (donate H in nonenzymatic reaction)
- Vitamin E (alpha-tocopherol)
- lipid soluble
- protects against lipid peroxidation
- Vitamin C (ascorbic acid)
- water soluble
- regenerates the reduced form of Vit E
- Carotenoids
- Uric acid
- Flavenoids
- Melatonin
