Biochemistry

Question 1

What are CYPs? What are the two most important CYP’s in humans and why?

Answer 1

Cytochrome P450 is a group of enzymes that uses iron to oxidise and thus solubilise xenobiotics

CYP3A4 for metabolism
CYP2D6 for polymorphisms

Question 2

What is the main organelle and organ for CYP detoxification?

Answer 2

ER in the liver

Question 3

In terms of its CYP:

• How does it distinguish between substrates
• What’s its prosthetic group?
• What’s its anchor group that binds Fe?
• What anchors it to the ER?

Answer 3

• Has an active site specific for particular classes of substrates
• Has a haem prosthetic group
• Cysteine anchor group
• Hydrophobic protein ‘foot’ anchors it to ER

Question 4

What enzyme gives CYP its electrons?

Answer 4

NADPH cytochrome P450 reductase

Question 5

What is the formula and steps for the phase 1 of detoxification that is CYP dependent?

Answer 5

RH + NADPH + H+ +2e- –> ROH + NADP+ + H2O
(so adding a hydroxyl to R the xenobiotic)

• NADPH is oxidised by CYP reductase.
• CYP receives the H+ and e- and uses one O to make H2)
• The other O+ is not reactive and can force reaction on substrate

Question 6

5-10% are deficient in CYP4D6, what kind of metaboliser does this make them? What can be the effects in a prodrug vs a drug?

Answer 6

Makes then poor metabolisers
In a pro drug it won’t get activated so will have little effect
In a drug it won’t get broken down so it’ll reach much higher concentrations with more toxic effects.

Question 7

In terms of CYP what can be the effective of being a ultra rapid metaboliser?

Answer 7

Can make drug ineffective due to low concentrations

Question 8

What are the 4 types of CYP metabolisers? Which one is ‘normal’?

Answer 8

• Poor metabolisers
• Intermediate metabolisers
• Extensive metabolisers (NORMAL)
• Ultra rapid metabolisers

Question 9

Where is the main site of RBC break down?

What does this?

Answer 9

The red pulp of the spleen.

Done by macrophages (mononuclear phagocyte system)

Question 10

What is Haem eventually broken down into?

Describe its structure

Answer 10

Bilirubin, an open chain of 4 pyrrole rings

Question 11

What is bilirubin conjugated with and with what enzyme in the liver to become? Why is it conjugated?

Answer 11

Conjugated with 2 UDP glucoconate by UDP gluconyltransferase to become bilirubin mono/diglucuronides
Makes it soluble as otherwise is very hydrophobic

Question 12

What is Crigler-Najjar syndrome a lack of? How do they treat it?

Answer 12

Lack of UDP glyconyl transferase
Treat with phototherapy which changes bilirubin from ZZ to EZ or EE which is more soluble and can go into bile unconjugated

Question 13

What is bilirubin converted into in the SI? Where do these 2 products go?

Answer 13

Into urobilinogen which goes to kidney and is excreted (becomes urobilin with O2)
Also into stercobilin which is excreted with the faeces.

Question 14

What causes Wernicke-Korsakoffs syndrome? What are some symptoms?
What % of australians exhibit it?

Answer 14

It is a neurotoxicity disorder from thiamine deficiency.
Alchohol is major cause.
Symptoms: uncoordinated eyes, confusion, amnesia, wide gait
2%

Question 15

What % of alcohol is metabolised in the liver?

What puts alcohol on your breath

Answer 15

> 90%

On breath as

Question 16

How can alcohol oxidation in the liver lead to hypoglycaemia?

Answer 16

The alcohol dedydrogenase in the liver produces NADH which suppresses gluconeogenesis (needed in the fasting state) and so you get hypoglycaemic.

Question 17

What is the microsomal ethanol oxidising system? When is it activated?

Answer 17

The up regulation of CYP 2E1 from chronic alcoholism.
It consumes NADPH so less energy is consumed.
Unregulated with sustained alcohol intake

Question 18

Why does alcohol dehydrogenase hit vmax after 2 hours? how much alcohol can it clear an hour once it’s reached?

Answer 18

Because its not inducible it reaches saturation and therefore vmax after about 2 drinks.
Clearance then is 0.015%/hr (1 drink/hour)

Question 19

What are the two alternate effects alcohol can have on drugs?

Answer 19

Decreased clearance when drinking alcohol (using the CYP E21)
Increased clearance once stopped drinking (as CYP E21 still elevated)

Question 20

What is the main liver enzyme thats used as a marker for alcohol intake?

Answer 20

Gamma- glutamlytranspeptidase (GGT)

Question 21

Why does alcohol cause dehydration?

Answer 21

It interferes with the pituitary so less antidiuretic is produced and more fluid is excreted.

Question 22

What causes gall stones?

Answer 22

When there is too much cholesterol and not enough bile salts in the bile and the cholesterol precipitates out.

Question 23

What is steatorrhea? What deficiency can it lead to?

Answer 23

Fat in the faeces, eg from no bile.

Can lead to deficiency of the fat soluble vitamins and essential fatty acids

Question 24

What are the two main causes of pancreatitis?

Answer 24

Gall stones blocking the pancreatic duct

Alcohol abuse

Question 25

In haemolytic jaundice what happens to the levels of?

• Unconjugated bilirubin
• Urobilirubin
• Haptoglobin

Answer 25

• Increase
• Increase
• Decrease

Question 26

What occurs in glucose 6-phosphate dehydrogenase deficiency and why?

Answer 26

• Haemolytic anemia

- Because it causes decrease in glutathione which is a powerful antioxidant so RBC die sooner

Question 27

Which congenital disorders cause unconjugated hyperbilirubinaemia vs congugated bilirubinaemia?

Answer 27

Unconjugated: Gilbert snad Crigle Najjar
Conjugated: Dubin-Johnson

Question 28

What is higher AST and ALT or ALP and GGT in:
Hepatocellular injury
Cholestasis

Answer 28

HI: ASL and ALT
CH: ALP and GGT

Question 29

Out of ALT and AST:

• Which one is in two locations within cell
• Which one has a longer half life

Answer 29

• AST in membrane and mitochondria

- ALT has longer half life