Session 4: Alcohol metabolism, oxidative stress and protein and amino acid metabolism

Question 1

Describe the metabolism of alcohol and how it can cause damage to the liver

Answer 1

Most alcohol is metabolised by the liver, rest is excreted through urine and breath. Alcohol is oxidised by alcohol dehydogenase to acetaldehyde, then acetate by aldehyde dehydrogenase. The acetate is converted to acetyl CoA and use in TCA cycle or for fatty acid synthesis. Acetaldehyde is toxic, and its accumulation leads to hangover effects and liver damage. Excess NADH and acetyl CoA lead to changes in liver metabolism- leads to fatty liver, hepatitis, alcoholic cirrhosis.

Question 2

Explain the mechanism of action of Disulfiram in the treatment of alcohol dependance

Answer 2

It is an inhibitor of aldehyde dehydrogenase, and will cause accumalation of acetaldehyde, leads to symptoms of hangover- associated with alcohol consumption

Question 3

Describe production of superoxide by mitochondria and discuss ROS and RNS.

Answer 3

In the Electron Transport Chain in the mitochondria, electrons generally combine with oxygen and protons to form water. However, some electrons prematurely reduce oxygen to form superoxide, a part of ROS. ROS and RNS damage nucelic acids, proteins and lipids

Question 4

How does ROS cause damage?

Answer 4

Electron prematurely combines with O2 to form superoxide. This then forms a hydroxyl radical through more rxns, which is very reactive.
Damage to DNA: ROS reacts with DNA and damages it, failure to repair can lead to mutation- cancer
Damage to proteins: ROS reacts with backbone and sidechain, protein degradation, change in structure of disulphide bonds, leads to loss or gain in function
Damage to lipids: ROS reacts with lipid, hydrophobic environment of bilayer disrupted and membrane integrity fails.

Question 5

How can free radicals be helpful at times?

Answer 5

1. Nitric oxide synthase: Nitric oxide( free radical) is toxic at high levels but also functions as a vasodilator, neurotransmitter
2. Respiratory burst: Rapid production of superoxide and hydrogen peroxide from phagocytic cells. ROS destroys invading bacteria, part of antimicrobial defence system.
   Chronic granulomatous disease: genetic defect in NADPH oxidase, cannot produce superoxides, increases suspectibility to bacterial infection likes pneumonia.

Question 6

Explain the cellular defenses against ROS

Answer 6

1. Glutathione: It is a tripeptide synthesised by body to protect against oxidative damage. Donates electron to RO, goes from reduced state GSH to GSSG. It then gets reduced back to GSH by the same enzyme that oxidises NADPH to from NADP. Therefore, NADPH from PPP is needed for protection against oxidative damage.
   PPP: importance source of NAPDH, required for detoification of rxns, reducing power for biosynthesis as it will undergo oxidation to form NADP. No ATP synthesis reuired, CO2 produced, rate is limited by Glucose-6-phosphate dehydrogenase enzyme
2. Free radical scavengers: Vitamin E(protects against lipid peroxidation), vitamin C(regenerates reduced form of vit E), melatonin and carotenoids. These scavengers donate H atoms ad electron to free radicals in nonenzymatic reaction

Question 7

Describe role of oxidative stress in disease states

Answer 7

1. Galactosaemia: Galactose is converted to galacticole by aldose reductase, which also converts NADPH to NADP+. Increased activity of reductase, decreases NADPH. Defense against ROS compromised, protein in eye lens denatures, leads to cataract, hypoglycaemia
2. G6PDH deficiency: low G6PDH activity, low NAPDH, leads to low GSH, less protection from oxidative damage
   3 Heinz bodies, haemolysis
   4 metabolism of paracetamol
   5 what causes oxidative damage