Lecture 5 Flashcards
Are xenobiotics often water soluble or not? Are they hydrophilic or hydrophobic?
Xenobiotics are not very water soluble. They are often hydrophobic.
Why do you need to metabolise xenobiotics?
To make them more water soluble and hydrophilic so it’s easier to get rid of them.
What is the difference between primary metabolism and secondary metabolism? Give examples.
Primary metabolism is essential for life while secondary is not.
Primary: citronsyracykeln, metabolism of glucose
Secondary: snake’s venom. It’s important for the snake to produce venom but it will not die immediately if it’s not produced.
Is the metabolism of xenobiotics primary or secondary?
It’s often secondary.
What are two other words for metabolism of xenobiotics?
Biotransformation and detoxification.
What phases can biotransformation be divided into?
Phase I and phase II.
What does phase I and phase II do?
It helps increase the water solubility so it gets easier to get rid of the molecule.
What is the problem with excretion of lipophilic compounds?
It can’t go out via the kidney.
What do phase I do? What happen with the water solubility of this compound?
Add a hydrophilic handle to the lipophilic compound. The water solubility increases.
What do phase II do? What happen with the water solubility?
An even larger hydrophilic part is added to the compound with the hydrophilic handle. The water solubility increases even more.
Give some examples of handles used in phase I.
Small, hydrophilic polar group. Like hydroxy group, amino group, karboxylsyra.
Give some examples of conjugates used in phase II.
Sugar units, they are very hydrophilic.
Do all molecules in the metabolism undergo both phase I and II?
No. For some, phase I might be hydrophilic enough. For others, they might already have a handle so they can go directly to phase II.
Place phenol, phenol-O-glucuronide and benzene where they belong in phase I, phase II and end product.
Benzene —> Phenol (OH: hydrophilic handle, phenol: major phase I metabolite) —> Phenol-O-glucuronide (major phase II metabolite).
Why is the enzyme cytochrome P-450 important?
- It is used in the liver to metabolise many xenobiotics.
2. It can catalyse oxidations and reductions (more ox. than red.)
Where is cytochrome P-450 present and what is the environment like?
It lives in the ER where it’s hydrophobic.
Why could it be dangerous when we have both ethanol and CHCl3 in our bodies?
They are catalysed by the same enzyme, cytochrome P-450, which gives it a stronger toxic effect.
How is the general oxidation performed by cytochrome P-450?
R-H + O2 → R-OH + H2O
)NADPH + H+ → NADP+) - coenzyme
Whats the coenzyme of cytochrome P-450?
NADPH
Name a example in our body where cytochrome P-450 is important for essential nutrients.
It help transform Vitamin D3 into calcitriol which regulates Ca uptake.
In what organ (mainly) can we find cyrochrome P-450?
In the liver.
What’s the mechanism of cytochrome P-450 to catalyze oxidation reaction? The enzyme has Fe(III) bound to it.
- The substate comes in (lipophilic association)
- bind to the lipophilic part of the enzyme. - An electron is added and Fe(III) is reduced to Fe(II)
- Receive 1 e- from NADPH cytochrome P-450 reductase —> reduce Fe(III) to Fe(II). - O2 binds to the Fe(II).
- Fe(II) has a good binding force with O2 - Fe(II) is oxidized to Fe(V) and the other O is reduced to water
- Receive 1 e- from NADPH cyrochrome P-450 reductase —> one O is reduced to H2O, the other one is used to oxidize Fe(II) into Fe(V) (very active oxidant). - Fe(V)=O oxidizes R-H
- Fe(V) the oxidize the substrate to from CH3 to OH and it become Fe(III). - The substrate then become more hydrophilic and is kicked out from the enzyme and the cycle repeats.
What is the problem with the cytochrome P-450 cycle?
If O2 get an e- from Fe(II) —> O2- gets kicked out because Fe(III) doesn’t have good affinity with oxygen.
O2- —> superoxide anion, ROS: dangerous
What does ROS stand for?
Reactive Oxygen Species.
