Polymorphisms and Toxic metabolites Flashcards
What is genotype determined by?
The individual DNA sequence
What is Phenotype distinguished by?
The activity or the amount of the expressed CYP
What categories define metabolic activity?
Extensive metaboliser
Poor metaboliser
Ultra-rapid metaboliser (higher xenobiotic metabolism)
What Xenobiotics can lead to an increased expression of enzymes of the CYP3A family and how?
- Indinavir (antiviral)
- Cyclosporin (immuno-suppressant)
- Carbamazepine (anticonvulsant)
- Atorvastatin (HMG CoA Reductase inhibitor)
- Tamoxifen (anti-hormone)
By binding to the pregnane X receptor (PXR) which is a transcription factor that regulates CYP3A gene expression
What is the process of PXR (Pregnane X receptor)?
The PXR receptor with the retinoid X receptor (RXR) acts as a heterodimer.
This causes the up-regulation of CYP3As .
This leads to an increased metabolism of substances.
Can cause adverse reactions
Why is Grape juice bad?
It is a potent CYP3A4 inhibitor and increases plasma peak drug concentration but not elimination.
Why is CYP2E1 unique among CYPs?
It is primarily located in the rows of 5 cells around the central venules of a liver lobule.
Any adverse effect will causes inflammation of the liver.
This is because it produces reactive oxygen radicals (ROS) through reduction of O2. These damage cells.
And it is strongly induced by ethanol
What kind of patients is CYP2E1 increased in?
Patients with diabetes, obesity and other nutritional states that produce acetone.
How can Ethanol be metabolised?
Using Alcohol dehydrogenase
or
CYP2E1
which results in acetaldehyde
Explain why Ethanol can be toxic?
The action of alcohol dehydrogenase and aldehyde dehydrogenase can lead to accumulation of NADH
They can inhibit gluconeogenesis, causing accumulation of lactate.
And upregulates fatty acid synthesis leading to fatty liver disease.
Explain how CYP and NADH can lead to Ethanol toxicity?
CYP pathway generates free radicals, consumes NADPH and depletes glutathione (GSH) levels
NADH leads to release of ketone bodies and high levels of acetaldehyde, resulting in liver damage and death.
Explain how Paracetamol can be toxic?
Paracetamol may be N-hydroxylated to give an unstable intermediate that rearranges to NAPQI
NAPQI is an electrophile and will react and attack nucleophilic centres, destroying them.
What removes NAPQI?
Glutathione
What are the antidotes for Paracetamol Toxicity?
N-acetylcysteine or methionine
Work by up-regulating the amount of Glutathione GSH through supply of cysteine
Addition cysteine = addition of GSH
Methionine is not actually required unless there is a risk of OD