Alcohol Metabolism & Oxidative Stress Flashcards
What are the 4 consequences of liver damage due to prolonged and excessive alcohol consumption
Hypoglycaemia
Gout
Lactic Acidosis
Fatty Liver
What 2 things are needed for Glutathione Peroxidase to work?
Selenium
NADPH
Why are free radicals so damaging
Very reactive, tend to Aquire electrons from other atoms/ molecules/ ions
Reaction of a radical with a molecule generates a second radical, thus Propagating damage
Where and how is alcohol metabolised?
Mostly by Liver, small amount excreted passively in urine and on breath
Smaller amounts by CYP2E1 OR by Catalase in brain
How many ethanol grams per alcohol unit?
What is the rate of elimination of ethanol?
What is the recommended intake of alcohol
Describe the pathway for alcohol metabolism
- 8g
- 7g per hour
- 14 units per week over at least 3 days
Alcohol Dehydrogenase Alcohol + NAD+ ——————————-—> Acetaldehyde + NADH Aldehyde Dehydrogenase Acetaldehyde + NAD+ ——————————-> Acetate + NADH
Acetate + CoA ———> Acetyl-CoA
Which intermediate of alcohol metabolism is toxic, what does it cause?
What are the 3 kinds of liver damage?
Acetaldehyde causes “Hangover” like symptoms
- Fatty Liver
- Alcoholic Hepatitis
- Alcoholic Cirrhosis
Excess of what 2 substances leads to changes in liver metabolism
NADPH
Acetyl-CoA
What is used to treat Chronic Alcohol Dependence?
How does it work
Disulfiram inhibits Aldehyde Dehydrognase leading to hangover like symptoms
What is Oxidative Stress?
Name some diseases it causes
Define a free radical
Imbalance between Free radicals and Antioxidants in the body
Cancer, MS, Cardiovascular Disease, Alzheimer’s, Parkinson’s
Atom or molecule that contains one unpaired electron and is capable of independent existence
What are the 2 types of Reactive Species?
ROS: Reactive Oxygen
RNS: Reactive Nitrogen
Name 3 ROSs and what do they do
How is the main one formed?
Superoxide, Produced by adding e- to Molecular O2
H2O2, Reacts with Fe2+ to make free radicals (Fenton Reaction)
Hydroxyl Radical, Most reactive and damaging free radical, reacts with anything
What are the 2 RNSs, how is one formed from another
- Nitric Oxide
- Peroxynitrite, a powerful oxidant that can damage cells
Made by Combing Nitric Oxide with Superoxide
How can a Reactive Species Damage DNA
- Reacts with and modifies base—> Mispairing and mutation
* Reacts with sugar—> Strand break and mutation on repair
How can a Reactive Species Damage Proteins
Reacts with protein;
- Backbone Fragmentation-> Protein Degradation
- Modified Side Chain-> Protein structure change—> Protein Degradation/ Function loss/ Function gain
How can a Reactive Species Damage Lipids
Outline the 3 steps
• Oxidative stress causes lipid peroxidation and a chain reaction that leads to cell membrane disruption
- Free radical removes H atom from fatty acid
- Lipid radical forms, reacts with O2 to form a Lipid Peroxyl radical
- Lipid Peroxyl removes H atom from a fatty acid, starting a chain reaction
Name 4 Exogenous Oxidants
Drugs
Toxins
Pollutants
Radiation
Name Endogenous Oxidants
NADPH Oxidases
Nitric Oxide Synthases
ETC (e- escape ETC and react with O2–> Superoxide-> OH radical
Compare the 3 types of Nitric Oxide Synthase
- conc.
- Function
eNOS: (Endothelial) Exists at low conc. Functions as a signalling molecule
nNOS: (Neuronal) Exists at low conc. Functions as a signalling molecule
iNOS: (Inducible) Produces high NO conc. in phagocytes
What is the Respiratory Burst
• Release of Superoxide, Nitric Oxide, H2O2 to destroy bacteria
What are 3 methods of cellular defences Against antioxidants
- Superoxide Dismutase (SOD) and Catalase
- Glutathione
- Free radical scavengers
How do Superoxide Dismutase and Catalse work
SOD: Superoxide—> O2 + Hydrogen Peroxide
Catalase: Hydrogen Peroxide—> O2 + Water
What is glutathione?
How does Glutathione work to defend against oxidative stress
A tripeptide consisting of Glycine, Cysteine, Glutamate
- Using Glucathione Peroxidase, a Reactive Species takes an e- from -SH (Thiol group) on cysteine
- Formation of Disulphide bond between 2 Glutathiones (GSH) to form a GSSG
- Glucathione Reductase transfers e- from NADPH to GSSG, re-forming 2 GSH molecules
How do free radical scavengers work?
Which 2 vitamins come under this category and how Do they work?
- Donate H atom and e- to free radicals in a non-enzymatic reaction
Vitamin E: Lipid Soluble antioxidant, protects against lipid peroxidation
Vitamin C: Water Soluble antioxidant, helps regenerate reduced form of Vitamin E
Compare Normal [Paracetamol] metabolism to High [Paracetmaol] Metabolism
Suggest a treatment for Paracetamol OD, and explain why it works
• NORMALLY, conjugated to Suplhate OR Glucoronide
- High Paracetamol—-> NAPQI accumulation
- NAPQI is conjugated to Glutathione for detoxification
• Acetylcysteine replenishes glutathione levels, so is a viable treatment
