Polymorphisms and Toxic metabolites Flashcards

1
Q

What is genotype determined by?

A

The individual DNA sequence

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2
Q

What is Phenotype distinguished by?

A

The activity or the amount of the expressed CYP

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3
Q

What categories define metabolic activity?

A

Extensive metaboliser

Poor metaboliser

Ultra-rapid metaboliser (higher xenobiotic metabolism)

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4
Q

What Xenobiotics can lead to an increased expression of enzymes of the CYP3A family and how?

A
  • 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

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5
Q

What is the process of PXR (Pregnane X receptor)?

A

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

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6
Q

Why is Grape juice bad?

A

It is a potent CYP3A4 inhibitor and increases plasma peak drug concentration but not elimination.

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7
Q

Why is CYP2E1 unique among CYPs?

A

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

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8
Q

What kind of patients is CYP2E1 increased in?

A

Patients with diabetes, obesity and other nutritional states that produce acetone.

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9
Q

How can Ethanol be metabolised?

A

Using Alcohol dehydrogenase

or

CYP2E1

which results in acetaldehyde

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10
Q

Explain why Ethanol can be toxic?

A

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.

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11
Q

Explain how CYP and NADH can lead to Ethanol toxicity?

A

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.

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12
Q

Explain how Paracetamol can be toxic?

A

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.

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13
Q

What removes NAPQI?

A

Glutathione

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14
Q

What are the antidotes for Paracetamol Toxicity?

A

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

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