Ligand metabolism and transport - PXR en CAR

4 important questions on Ligand metabolism and transport - PXR en CAR

What are ligands of PXR?

  • Pregnane (steroid)
  • Adrostane (steroid)

So, CAR and PXR can induce CYP enzymes. Name some characteristics of CYP34A. (6)

  • Induced and thus expressed only in the presence of PXR ligand = bijvoorbeeld rifampicin
  • It moves to the endoplasmatic reticulum.
  • Important for oxidation (phase I)
  • Important for lipophilic drugs
  • Can bioactivate compounds to become more toxic.
  • Grapefruit= competitive inhibitor of CYP3A4

Where is CYP3A4 expressed?

Liver and GI tract.
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A transporter is also induced by PXR. Which one and name some characteristics (6)

P-Glycoprotein ABCB1 (aka MDR1)
  • Induced by PXR agonist - rifampicin
  • 170 kDa transmembrane glycoprotein
  • Widely expressed including liver
  • Efflux pump
  • ATP dependent (active), broad substrate specificity
  • Many CYP3A4 substrates are also P-gly substrates – can be issues with drug drug interactions as both export and metabolism affected.     

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