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Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood-brain barrier after CITCO activation

Julia Lemmen1, Iasson E P Tozakidis, Prachee Bele

  • 1International Graduate School (GRK 1409/2), Westfälische Wilhelms-Universität Von-Esmarch-Str. 56, D-48149 Münster, Germany.

Brain Research
|January 24, 2013
PubMed

Insights

Constitutive androstane receptor (CAR) activation by the human ligand CITCO up-regulates ABC-transporters like P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in brain endothelial cells, impacting CNS drug delivery.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • ATP-driven efflux transporters, including Abcb1 (P-glycoprotein) and Abcg2 (breast cancer resistance protein), are key regulators of blood-brain barrier (BBB) permeability.
  • These transporters protect the brain from toxins but also impede central nervous system (CNS) drug efficacy.
  • Understanding the regulation of these efflux transporters is crucial for improving CNS pharmacotherapy.

Purpose of the Study:

  • To investigate the effect of the nuclear receptor CAR (constitutive androstane receptor) on the expression and activity of Abcb1 and Abcg2 in porcine brain capillary endothelial cells (PBCEC).
  • To determine if human-specific CAR activation influences these efflux transporters relevant to CNS drug penetration.

Main Methods:

  • Primary cultures of porcine brain capillary endothelial cells (PBCEC) were utilized.
  • Cells were treated with specific ligands for CAR: CITCO (human CAR activator) and TCPOBOP (mouse CAR activator).
  • Expression levels of Abcb1 and Abcg2 were analyzed at RNA, protein, and transport activity levels. CAR inhibitor was used to confirm specificity.

Main Results:

  • Activation of porcine CAR by the human-specific ligand CITCO significantly upregulated both Abcb1 and Abcg2 expression and activity in PBCEC.
  • The mouse-specific CAR ligand TCPOBOP showed no effect on transporter expression.
  • Inhibition of CAR reversed the observed upregulation, confirming CAR's role.

Conclusions:

  • Human CAR activation by CITCO effectively increases the expression and activity of key efflux transporters (Abcb1 and Abcg2) in brain endothelial cells.
  • This finding highlights a potential mechanism influencing drug efflux at the BBB and has implications for CNS drug development strategies.

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