Oxidative stress and alcohol metabolism

Question 1

Where is the majority of alcohol metabolised? By what and where is a small amount metabolised? Also, what two mechanisms does alcohol pass the metabolism?

Answer 1

In the liver

Small amount metabolised by cytochrome p450 and catalase in the brain

some lost in breath and urine

Question 2

Describe the alcohol metabolism. Products, enzymes and what is produced as well>

Answer 2

alcohol–>acetaldehyde–>acetate
Alcohol dehydrogenase
aldehyde dehydrogenase

In the process, NAD+–>NADH

Question 3

What chemical causes a hangover?

Answer 3

acetaaldehyde

Question 4

What two things does acetate go on to do?

Answer 4

TCA cycle or FA synthesis

Question 5

what metabolite causes liver damage. What three conditions can excessive alcohol consumption lead to?>

Answer 5

Acetaldehyde
Fatty liver
alcoholic hepatitis
alcoholic cirrhosis

Question 6

Describe the metabolic changes that occur due to alcohol consumption (Due to two factors)

Answer 6

Decreased NAD+:NADH ratio
Leads to…
-Decreased conversion of Lactate to pyruvate –>increased lactate concentration of the blood–>lactic acidosis
Also increased lactate concentration–>the kidneys ability to remove uric acid to decrease–>urate crystals to build up–>gout

• Decreased NAD+ for glycerol metabolism–>Less gluconeogenesis–>Hypoglycaemia
• Less NAD+ for fatty acid oxidation–>increased synthesis of TAGs–>Fatty liver

Also increased Acetyl coA
-Increased FA synthesis–>Increased TAG–>Fatty liver

Question 7

Describe a treatment for alcohol dependence?

Answer 7

Disulfiram

Inhibits aldehyde dehydrogenase, so acetaldehyde build up–>hangover whilst drinking

Question 8

Name four diseases linked to oxidative stress

Answer 8

Cancer
Crohns disease
Cardiovascular disease
Ischaemic/reperfusion injury

Question 9

Define free radical

Answer 9

an atom or molecule that contains one or more unpaired electrons and is capable of free existence

Question 10

Name 3 ROS and 2 Reactive nitrogen species

Answer 10

ROS- Superoxide, Hydrogen peroxide and Hydroxyl radicals

RNS- Nitric oxide and peroxynitrite (ONOO-)

Question 11

Two main types of damage of ROS to DNA?

Answer 11

ROS reacts with base–>mispairing and mutation

ROS reacts with sugar(Ie ribose or deoxyribose)–>strand break and mutation on repair

Question 12

Explain how ros can damage proteins

Answer 12

Can damage backbone or sidechain

to backbone, can cause fragmentation–>protein degradation

to sidechain–>Can modify amino acids by eg. adding disulphide bonds, dimers, carbonyls etc..
leads to change in protein structure–>protein degradation, loss of function or gain of function

Question 13

What types of groups do disulphide bonds form between?

Answer 13

Thiol groups on cysteine residues

Question 14

What three things can inappropriate disulphide bond formation lead to?

Answer 14

Misfolding, cross linking and disruption of function

Question 15

How can ROS damage lipids?

Answer 15

Free radical takes hydrogen atom from a polyunsaturated FA in the membrane lipid

Causes a chain reaction

The hydrophobic enviroment and bilayer gets disrupted and membrane integrity fails

Question 16

Name three endogenous sources of biological oxidants and three exogenous sources

Answer 16

Endogenous: Electron transport chain
Nitric oxide synthases
NADPH oxidases

Exogenous: Radiation (EG. Cosmic rays, X-rays)
drugs
toxins

Question 17

Explain how the electron transport chain can be a source for biological oxidants

Answer 17

NADH and FADH2 supply electron
pass through the elctron transport chain
can occasionally escape chain and react with dissolved oxygen–>superoxide

Question 18

What enzyme can make Nitric oxide? What three things is nitric oxide used for? How is nitric oxide made?

Answer 18

Nitric oxide synthase
Arginine converted to citrulline and Nitric oxide

Nitric oxide used for: Vasodilation
neurotransmission
S-Nitrosylation

Toxic at high levels

Question 19

What is a respiratory burst?

Answer 19

Rapid release of superoxide and Hydrogen peroxide from phagocytic cells
destroy invading bacteria

Question 20

What is the cause of chronic granulomatous disease? What can this lead to?

Answer 20

Defect in NADPH oxidase complex
leads to enhanced susceptibility to bacterial infections

eg. Pneumonia, abscesses, impetigo, cellulitis

Question 21

Name three cellular defences against ROS

Answer 21

Superoxide dismutase
Catalase
Glutathione

Question 22

Explain how superoxide dismutase acts as a cellular defence

Answer 22

Converts superoxide to H2O2 and oxygen

Question 23

Explain how catalase acts as a cellular defence

Answer 23

Converts H2O2 to water and oxygen

Question 24

Explain how glutathione acts as a cellular defence

Answer 24

The thiol group of glutathione donates an electron to the ROS
reacts with another glutathione in the process
-the enzyme glutathione peroxidase catalyses this reaction. Forms GSSG (GSH–>GSSG)

GSSG–>GSH using glutathione reductase. Requires NADPH–>NADP+

Question 25

Why is the pentose phosphate pathway important in celular defences?

Answer 25

Provides NADPH for the reduction of GSSG-->GSH | Enzyme Glutathione reductase catalyses this

Question 26

Whhat two vitamins are important cellular defences?

Answer 26

vit C and E

Question 27

Describe how galactosemia causes cataracts

Answer 27

Galactose accumulates requires the alternative pathway to be metabolised aldose reductase convert galactose to galactitol uses NADPH-->NADP+ so decreased NADPH levels so less GSSG converted back to GSH oxidative damage to cystallin protein in the eye

Question 28

Explain how a G6PDH deficiency can lead to more damage from oxidative stress

Answer 28

G6PDH converts 2NADP+-->2NADPH So deficiency in this enzyme-->decreased NADPH Decreased NADPH means less GSSG converted to GSH so less protection to oxidative stress

Question 29

What is the clinical sign of G6PDH deficiency?

Answer 29

Heinz bodies

Question 30

What is paracetemol normally broken down to at the prescribed dose?

Answer 30

Sulphate and glucuronide

Question 31

What builds up and causes damade in a paracetemol overdose? What type of damage does it cause?

Answer 31

NAPQI | Oxidative damage

Question 32

What is the treatment for paracetemol overdose?

Answer 32

Acetylcysteine | Replenishes glutathione levels to combat oxidative stress