Reactive oxygen species - Drug metabolism enzyms
12 important questions on Reactive oxygen species - Drug metabolism enzyms
What is happening during the phase I and II of drug metabolism related to ROS?
ð Sometimes this process goes wrong => O2-, H2O2, OH.
Phase II metabolism: conjugation reactions—such as glucuronidation, sulfation, and glutathione conjugation
- making compounds more water-soluble for excretion.
- Reactive products are instable and can bound to proteins or DNA => cojugations prevents this.
Which enzymes are involved during the two different phases?
Phase II: GSH (glutathion)(heeft ook een anti-oxidant functie), UGT
What does the gluthatione (GSH)? (3 roles)
- Radical scavenger
- Co-substrate for enzymatic degradation of H2O2.
- Keeps cells in reduced state and involved in regeneration of oxidized proteins.
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What is different between the metabolism of paracetamol/acetaminophen and diclofenac?
- Inactivation by GSH (glutathion) = phase II
- results in stable metabolites
Diclofenac => metabolized in two different ways => CYP2C9 and P450. Into quinone imine
Quinone imine has a double bond => trigger electrons donated for oxygen => oxidated stress (might also be linked to proteins)
- metabolism by UGT enzymes= phase II
- results in stable metabolites
What experiment was done on the diclofenac metabolism?
- So, diclofenac is metabolized by UTG and CYP2C9. These two have specific inhibitors
BOR: borneol = UGT inhibitor
SUL: sulfaphenzole = CYP2C9 inhibitor.
- The two metabolites were measured.
- They found out that adding the inhibitor indeed results in less metabolites, related to the product and the specific enzyme that is needed.
Did this inhibition of the enzymes also result in less covalent adducts? What do we learn from this?
They also saw less LDH leakage = less damaged cells.
CYP- enzymes we need. But during the period between phase I and II they are also dangerous.
What are the different defence lines against drug-induced stress?
- Drug metabolism: Basal expression of genes for phase II enzymes (GSH, glutathion), (NRf2), NF-kB( transcription factor)
- Antioxidant response: Induction of genes for phase II enzymes (ROS: MAPK=> cytokines)
- Apoptosis
What is the role of NRF2 in the defence of drug induced stress?
- Activates expression of antioxidants
- Activates detoxification enzymes
- NRF2 is bound to KEAP1
- After activation it bounds to ARE (antioxidant response elements)
- ARE activates Glutathion synthese enzymes (GSH)
NF-kB, AP-1 and MAPK kinase also have a role, what role?
AP-1: co-activated with NF-kB
MAPK kinase:
What is risky about quinones?
- Redox cycling.
Quinone can take up an electron very easy => semi-Quinone
- Give it to oxygen => reactive oxygen
- And take it back again.
What do quinones with glutathion (GSH)?
- Take an electron from GSH
- GSH bind with glutathion
Risk of deprivation.
What is a risk of binding for quinone?
- Structural changes
- functional changes
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