Biochem Flashcards
What are the urinary and digestive system effective at removing and what aren’t they good at?
The urinary system and digestive system are good at removing soluble compounds, such as urea, but not good for hydrophobic compounds
What are hydrophobic toxins called?
Xenobiotics
What is phase I detoxification?
CYPs catalyse a range of reactions: hydroxylation, epoxidation, dealkylation& oxidation
=> makes toxins more soluble
What does a typical cytochrome p450 catalysed reaction look like?
RH + NADPH + H+ + O2 → ROH + H2O + NADP+
What is phase II detoxification?
Addition of a sugar (egglucuronate) to the –OH group makes the foreign molecule even more soluble
How many CYPs do humans have?
How many different families are these from?
49
17
What is the most important CYP in humans - what does it do?
CYP3A4 - metabolism
These are inducible upon exposure to appropriate substances
What is the most important CYP in terms of polymorphisms - what does that mean?
CYP2D6
There is considerable variation in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence for drugs that are metabolized by CYP2D6 will show variation in processing time
What is the main organ for CYP mediated detox?
Liver
Which organelle plays the most important detox role?
ER
From which Microsomes are derived
What is common to all cytochrome P450s?
An active site that is specificfor a particular class of substrate
A haem prosthetic group with iron that alternates between Fe2+ and Fe3+ as electrons are donated to oxygen.
A cysteineanchor (-CH2-SH) from the protein that forms a ligand to the Fe in haem (the side chain sulphurcoordinates to Fe
A hydrophobic protein “foot”that anchors the P450 to the ER membrane
What are the steps involved in a P450 reaction?
Step 1 -NADPH is oxidised by cytochrome P450 reductase (releases H+and 2 e-)
Step 2 -The H+and 2 e-are used by CYP to reduce one of the two atoms of molecular oxygen to water.
Step 3 -The other oxygen atom is retained in a highly reactive form, and used to force a reaction (eg hydroxylation) on the substrate.
What are the major P450 reactions?
1) hydroxylation (MAIN!!!)
2) Aromatic hydroxylation
3) Epoxidation - Has double bonds which can then react with DNA
4) De alkyation,
What are the minor P450 reactions?
1] N-oxidation,
2] Sulfoxidation,
3] Dehalogenation
Name an example of a toxin created by CYP450
Aspergillusfungus on corn & peanuts makes aflatoxin
→ Converted to aflatoxin B1 epoxide by P450
→ Reacts with DNA
→ Mutagen
Define a poor metaboliser
Homozygous for one deficient allele or heterozygous for two different deficient alleles (4% of caucasians)
Define an intermediate metaboliser
Heterozygous for one deficient allele or carry two alleles that cause reduced activity (32%)
Define an extensive metaboliser
Two wild-type alleles (55%)
Define an ultra rapid metaboliser
Multiple gene copies (9 %)
What percentage of the population have inactive CYP2D6 - what is the consequence?
5-10%
Codeine has no analgesic action unless some is converted to morphine by the action of CYP 2D6. => Poor metabolisers get no relief from codeine
CYP2D6 deficient patients also fail to metabolise about 25 other drugs
What problem do ultra rapid metabolisers have?
They can rapidly destroy some drugs, making them ineffective due to too low concentration
- This is especially true with antidepressants and antipsychotics
What is a side effect of SSRIs with regard to CYPs
Some Selective Serotonin Reuptake Inhibitors (SSRI antidepressants) such as Prozac inhibit many CYPs (espCYP2D6)
This makes “extensive metabolisers” resemble “poor metabolisers”
=> contraindicated with other CYP2D6-metabolised drugs such as tricyclic antidepressants and antipsychotics
Why is grapefruit contraindicated when taking a number of drugs?
Grapefruit contains furanocoumarin, which inhibits CYP 3A4
What do cruciferous vegetables (brussels sprouts, Kale, cabbage etc) induce?
Induce the expression of CYP1A2
=> May decrease bioavailability of drugs such as haloperidol (an antipsychotic)
What are some other functions of CYPs?
CYPs are involved in vascular autoregulation, particularly in the brain.
CYP are involved in the formation of cholesterol, steroidsand arachidonic acid metabolites (in mitochondria, especially in the adrenals)
What is erythropoietin?
It is a hormone which is secreted by the kidney.
Signals via JAK2, required for survival, proliferation + differentiation of committed erythroid progenitors; major function is to promote erythroid differentiation + initiate Hb synthesis
What is erythropoiesis?
Broduction of RBCs Stem cell (pluripotent blast cell, not multipotent) -> RBC (7 days) = 2 million/ day
What are the stages of haemapoeitic stem cell development?
Blast cell (stem cell) -> proerythroblast (large cell) -> polychromatic erythroblast (slightly smaller) -> matures by expelling its nucleus + digesting its nucleus -> reticulocyte (immature red cell) -> 1 day later -> RBC (7-10um)
What is MetHaemoglobin?
It is a heam molecule with a Fe3+ iron. This has no value in carrying oxygen and is thus recycled
What are the regions of the spleen called?
White pulp
Red Pulp
What is the role of white pulp?
Contains T cells, B cells and accessory cells -> similar to LN but captures blood-borne antigens b