1 - Oxidative Stress and Alcohol Flashcards
How is alcohol mainly metabolised?
Mostly in the liver
What are the minor ways of alcohol being removed from the body?
- Through urine or breath
- Catalase in the brain
- CYP450 called CYP2E1
What is one unit of alcohol and what is the elimination rate?
- 8g
- 7g/hour elimination
How are acetaldehyde levels kept low?
Acetaldehyde dehydrogenase has low Km
What are three things that can happen to the liver during excess alcohol consumption?
- Cirrhosis (scarring)
- Alcoholic Hepatitis
- Fatty Liver
What are the metabolic repsonses to excess alcohol consumption?
- Lactic Acidosis
- Hypoglycaemia
- Urate crystals so gout
- Fatty liver
What is one way to treat chronic alcohol consumption?
- Disulfiram
- Inhibits aldehyde dehydrogenase so will be build up of acetaldehyde leading to hangover if they drink
What diseases can oxidative stress cause?
When oxidative stress is more than cell defences (antioxidants):
- Parkinsons
- MS
- Cardiovascular disease
- Rheumatoid arthirities
- Pancreatitis
- Cancer
- Crohn’s
- COPD
What is a free radical?
Species with an unpaired electron, acquires electrons from other molecules. Therefore it generates a second free radical which normally causes the damage
What are the main oxidants that cause oxidative stress?
What does ROS damage?
- DNA
- Proteins
- Lipids
How does ROS cause damage to DNA?
- Reacts with base modifying it (mispairing)
- Reacts with sugar (strand break or mutation on repair)
How do you measure the amount of oxidative stress in a cell?
Amount of 8-oxo-dG
How doe ROS damage proteins?
How can disulphide bonds cause problems with function?
- Misfolding
- Crosslinking
How do ROS cause damage to lipids?
Lipid Peroxidation
1. Free radical (OH-) takes H atom from unsaturated membrane lipid
2. Generates lipid free radical
3. Free radical reacts with O2 to form lipid peroxyl radical
4. Chain reaction as free radical reacts with nearby phospholipid forming lipid peroxides
5. Disrupts hydrophibic environment so membrane integrity fails
What are some sources of biological oxidants?
Endogenous:
- ETC
- NO synathases
- NADPH Oxidases
- Peroxidase
- Lipooxygenases
- MAO
- Xanthine Oxidase
Exogenous:
- Radiation (UV, X-rays)
- Pollutants
- Drugs (primaquine - antimalarials)
- Toxins (paraquat - herbicide)
How is the ETC a source of oxidative stress?
Electrons can escape the chain and react with dissolved oxygen to form superoxide
How is nitric oxide synthase a source fo ROS?
What is respiratory burst?
Rapid release of superoxide and H2O2 from monocytes and neutrophils. ROS and Peroxynitrite destroy bacteria
What is chronic granulomatous disease?
Genetic defect in NADPH oxidase leading to susceptibility to bacterial infections
- Pneumonia
- Abscesses
- Cellulitis
- Impetigo
- Atypical infections
How does the cell defend itself from oxidative burst?
- SOD and Catalase
- SOD made from Cu and Zn in cytosol and extracellular. Made from Mn in mitochondria
(declining catalase in hair follicles could cause grey hair)
What is Glutathione?
- Tripeptide of Gly-Cys-Glu
- Thiol group donates e- to ROS then reacts with another GSH to form GSSG
What is NADPH used for?
- Detoxification reactions
- Biosynthesis reducing power
- Maintaining GSH
What is needed and what is produced from PPP?
- Starts with G-6-P
- CO2, C5 Sugars and NADPH produced
- No ATP
What are free radical scavengers?
- Vitamin E - Lipid soluble and protects against lipid peroxidation
- Vitamin C (ascorbic acid) - Water soluble regenerating reduced viamin E
Donate H atom to free radicals in a non-enzymatic reaction
What does a G6PDH deficiency lead to?
- Haemolysis due to lipid peroxidation (mechanial stress) and protein damage (heinz bodies)
- Can be genetic, infection, drugs and broad beans
What do heinz bodies look like histologically?
How is paracetamol metabolised and how do you overcome an overdose?
Acetylcysteine administration preferably in 2-8 hours. Over 8 hours may die from liver damage
How can anaemia lead to jaundice?
More red blood cells broken down, more bilirubin produced and therefore jaundice
