Alcohol Metabolism And Oxidative Stress

Question 1

Site of alcohol metabolism

Answer 1

Liver

Question 2

How is alcohol excreted

Answer 2

Urine
Passively on the breath
Oxidised by cytochrome P450 2E1 enzyme or catalase in the brain

Question 3

Recommended units of alcohol per week

Answer 3

14

Question 4

1 unit = how much ethanol

Answer 4

10ml (8g)

Question 5

Elimination rate of alcohol

Answer 5

7g per hour

Zero order kinetics

Question 6

Enzyme converting alcohol to acetaldehyde

Answer 6

Alcohol dehydrogenase

Reducing NAD+ to NADH

Question 7

Enzyme oxidising acetaldehyde to acetate

Answer 7

Aldehyde dehydrogenase
NAD+ reduced to NADH

Very low Km

Question 8

Effects of prolonged excessive alcohol consumption

Answer 8

Fatty liver
Alcoholic cirrhosis
Alcoholic hepatitis

Question 9

Effects of decrease in NAD+/NADH ratio

Answer 9

• reduced conversion of lactate to Pyruvate - lactic acidosis and gout
• reduced glycerol metabolism - decreased gluconeogenesis - hypoglycaemia
• reduced beta oxidation of fatty acids

Question 10

Effects of increase in acetyl coenzyme A

Answer 10

• fatty acid accumulation causing fatty liver as lack of lipoprotein synthesis

Question 11

Damaged liver cells

Answer 11

• leaky plasma membrane - transaminase and gamma glutamyl transpeptidase in blood (marker)
• reduced uptake and conjugation of bilirubin - jaundice
• reduced urea production - hyperammoneamia
• reduced protein synthesis - low serum albumin, clotting factors and lipoproteins
• low albumin - oedema
• low CF - increased prothrombin time
• low lipoproteins - fatty liver

Question 12

Direct effects of alcohol on GI

Answer 12

Damage cells lining the GI

Diarrhoea
Loss of appetite
Less absorption of nutrients e.g vitamin K
Thiamine - neurological symptoms - wernicke’s Korsakoff syndrome
Folic acid - macrocytic anaemia

Question 13

Direct damage to pancreas

Answer 13

Chronic pancreatitis

Question 14

Treatment

Answer 14

Disulfiram used as adjunct
Inhibits aldehyde dehydrogenase
accumulation of acetaldehyde - hangover symptoms

Question 15

Free radicals

Answer 15

Species with an unpaired electron that can exist independently
Very reactive
Causes damage to cells
Can propagate further radicals causing a chain reaction of damage

Question 16

Reactive oxygen species

Answer 16

Oxygen — superoxide (O2-) — hydrogen peroxide (H2O2) —hydroxyl radical (OH) and water — water

Question 17

Hydroxyl radical

Answer 17

Most reactive and damaging free radical

Question 18

Hydrogen peroxide

Answer 18

Not free radical but can react with Fe2+ to produce free radical

Question 19

Biradical

Answer 19

2 unpaired electrons in different orbitals with different spins
Eg molecular oxygen

Question 20

Sources of biological oxidants

Answer 20

Exogenous
Ionising Radiation
Toxins - herbicide eg Paraquat produces superoxide

Question 21

Reactive nitrogen species

Answer 21

Superoxide (O2-) + nitric oxide (NO) —> peroxynitrite (ONOO-)

Question 22

Types of damage by ROS

Answer 22

DNA
Proteins
Lipids

Question 23

DNA damage by ROS

Answer 23

Reacts with base - mismatch mutation
Reacts with sugar - double strand break - mutation on repair

Cancer

Amount of 8-oxo-dG used as a marker for oxidative damage

Question 24

ROS damage to proteins

Answer 24

React with protein backbone - fragmentation - degredation

React with side chains - modified amino acid - change in structure, function

Question 25

Heinz bodies

Answer 25

ROS stakes an electron from cysteine Think group more reactive Inappropriate Disulfide bonds formed Misfolding and cross linking Heinz bodies accumulate - precipitated cross linked Hb

Question 26

Lipid peroxidation

Answer 26

1. Free radical extracts electron from a polyunsaturated FA 2. Lipid radical formed 3. Reacts with oxygen to form lipid peroxyl radical 4. Chain reaction as lipid peroxyl radical reacts with another FA Hydrophobic environment disrupted in membrane bilayer - reduced integrity

Question 27

Endogenous sources of oxidants

Answer 27

``` Electron transport chain Nitric oxide syntheses NADPH oxidases - produces superoxide (resp burst) Peroxidases Lipoxygenases ```

Question 28

Nitric oxide syntheses

Answer 28

Inducible NO synthase - phagocytes direct toxic effect Endothelial NO synthase - vasodilator Neuronal NO synthase - signalling

Question 29

NO synthesis

Answer 29

Arginine —> citruline + NO* Using nitric oxide synthase NADPH oxidised to NADP

Question 30

Respiratory burst

Answer 30

1. Phagosome uses NADPH oxidase in cell membrane to convert NADPH to NADP and donate electron to oxygen to form superoxide 2. Phagosome engulfs bacteria 3. Superoxide converted to hydrogen peroxide 4. Secretory granules containing myeloperoxidase converts hydrogen peroxide to hypochlorite HOCl* which destroys bacteria

Question 31

Galactosaemia

Answer 31

Increased activity of aldose reductase uses up NADPH Less NADPH available for GSSG therefore glutathione recycled less More susceptible to oxidative damage

Question 32

Glucose 6 phosphate deficiency

Answer 32

Deficiency in G6P dehydrogenase in pentode phosphate pathway Produce less NADPH Less glutathione recycled More susceptible to oxidative damage

Question 33

Cellular defences against free radicals - antioxidants

Answer 33

``` Superoxide dismutase Glutathione Vitamin C and E Carotenoids, melatonin, uric acid, flavonoids Catalase ```

Question 34

Superoxide dismutase

Answer 34

Converts superoxide to hydrogen peroxide, oxygen and water

Question 35

Catalase

Answer 35

Hydrogen peroxide to water and oxygen | In immune cells to protect against respiratory burst

Question 36

Glutathione

Answer 36

Glycine - cysteine - glutamate Reduced form - SH Oxidated form - GSSG 1. Thiol group donates electron to ROS 2. GSH reacts with another GSH to form GSSG using glutathione peroxidase - requires selenium Glutathione reductase converts GSSG back to 2 x GSH using NADPH

Question 37

Vitamin E

Answer 37

Free radical scavenger Reduces lipid radicals by donating an electron Protects against lipid peroxidation

Question 38

Vitamin C

Answer 38

Regenerates Vitamin E reduced form

Question 39

Causes of oxidative stress

Answer 39

Infection Anti malaria drugs Broad beans

Question 40

Effects of oxidative stress

Answer 40

Lipid peroxidation - loss of cell membrane integrity - deformed Heinz bodies - haemolysis

Question 41

Metabolism of paracetamol at prescribed dosage

Answer 41

Metabolised in the liver by conjugation with glucuronide or sulphate

Question 42

Overdose of paracetamol (10g)

Answer 42

Converted to NAPQI oxidising agent Toxic to hepatocytes - conjugates with glutathione - less available antioxidant - covalent binding in hepatic proteins

Question 43

Treatment of paracetamol overdose

Answer 43

Acetylcysteine - replenish glutathione