Biochemistry Flashcards
What are CYPs? What are the two most important CYP’s in humans and why?
Cytochrome P450 is a group of enzymes that uses iron to oxidise and thus solubilise xenobiotics
CYP3A4 for metabolism
CYP2D6 for polymorphisms
What is the main organelle and organ for CYP detoxification?
ER in the liver
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?
- 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
What enzyme gives CYP its electrons?
NADPH cytochrome P450 reductase
What is the formula and steps for the phase 1 of detoxification that is CYP dependent?
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
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?
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.
In terms of CYP what can be the effective of being a ultra rapid metaboliser?
Can make drug ineffective due to low concentrations
What are the 4 types of CYP metabolisers? Which one is ‘normal’?
- Poor metabolisers
- Intermediate metabolisers
- Extensive metabolisers (NORMAL)
- Ultra rapid metabolisers
Where is the main site of RBC break down?
What does this?
The red pulp of the spleen.
Done by macrophages (mononuclear phagocyte system)
What is Haem eventually broken down into?
Describe its structure
Bilirubin, an open chain of 4 pyrrole rings
What is bilirubin conjugated with and with what enzyme in the liver to become? Why is it conjugated?
Conjugated with 2 UDP glucoconate by UDP gluconyltransferase to become bilirubin mono/diglucuronides
Makes it soluble as otherwise is very hydrophobic
What is Crigler-Najjar syndrome a lack of? How do they treat it?
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
What is bilirubin converted into in the SI? Where do these 2 products go?
Into urobilinogen which goes to kidney and is excreted (becomes urobilin with O2)
Also into stercobilin which is excreted with the faeces.
What causes Wernicke-Korsakoffs syndrome? What are some symptoms?
What % of australians exhibit it?
It is a neurotoxicity disorder from thiamine deficiency.
Alchohol is major cause.
Symptoms: uncoordinated eyes, confusion, amnesia, wide gait
2%
What % of alcohol is metabolised in the liver?
What puts alcohol on your breath
> 90%
On breath as
How can alcohol oxidation in the liver lead to hypoglycaemia?
The alcohol dedydrogenase in the liver produces NADH which suppresses gluconeogenesis (needed in the fasting state) and so you get hypoglycaemic.
What is the microsomal ethanol oxidising system? When is it activated?
The up regulation of CYP 2E1 from chronic alcoholism.
It consumes NADPH so less energy is consumed.
Unregulated with sustained alcohol intake
Why does alcohol dehydrogenase hit vmax after 2 hours? how much alcohol can it clear an hour once it’s reached?
Because its not inducible it reaches saturation and therefore vmax after about 2 drinks.
Clearance then is 0.015%/hr (1 drink/hour)
What are the two alternate effects alcohol can have on drugs?
Decreased clearance when drinking alcohol (using the CYP E21)
Increased clearance once stopped drinking (as CYP E21 still elevated)
What is the main liver enzyme thats used as a marker for alcohol intake?
Gamma- glutamlytranspeptidase (GGT)
Why does alcohol cause dehydration?
It interferes with the pituitary so less antidiuretic is produced and more fluid is excreted.
What causes gall stones?
When there is too much cholesterol and not enough bile salts in the bile and the cholesterol precipitates out.
What is steatorrhea? What deficiency can it lead to?
Fat in the faeces, eg from no bile.
Can lead to deficiency of the fat soluble vitamins and essential fatty acids
What are the two main causes of pancreatitis?
Gall stones blocking the pancreatic duct
Alcohol abuse
In haemolytic jaundice what happens to the levels of?
- Unconjugated bilirubin
- Urobilirubin
- Haptoglobin
- Increase
- Increase
- Decrease
What occurs in glucose 6-phosphate dehydrogenase deficiency and why?
- Haemolytic anemia
- Because it causes decrease in glutathione which is a powerful antioxidant so RBC die sooner
Which congenital disorders cause unconjugated hyperbilirubinaemia vs congugated bilirubinaemia?
Unconjugated: Gilbert snad Crigle Najjar
Conjugated: Dubin-Johnson
What is higher AST and ALT or ALP and GGT in:
Hepatocellular injury
Cholestasis
HI: ASL and ALT
CH: ALP and GGT
Out of ALT and AST:
- Which one is in two locations within cell
- Which one has a longer half life
- AST in membrane and mitochondria
- ALT has longer half life
