Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth...

Area of Science:

• Pharmacology
• Molecular Biology
• Hepatology

Background:

• The constitutive androstane receptor (CAR) regulates xenobiotic and endobiotic metabolism.
• CAR activation occurs directly via ligand binding or indirectly through epidermal growth factor (EGF) signaling inhibition.
• Leflunomide (LEF) and teriflunomide (TER) are used to treat autoimmune diseases.

Purpose of the Study:

• To investigate if teriflunomide (TER), an EGF receptor antagonist, acts as an indirect activator of the constitutive androstane receptor (CAR).
• To determine the mechanism by which LEF and TER modulate CAR activity and target gene expression.

Main Methods:

• Primary human hepatocytes and differentiated HepaRG cells were used to study CAR target gene expression (CYP2B6, CYP3A4).
• Gene reporter assays assessed CAR ligand binding domain (LBD) and CAR3 variant activation.
• CAR+A mutant translocation and CAR mRNA expression were analyzed.

Main Results:

• LEF and TER up-regulated CAR target genes CYP2B6 and CYP3A4 mRNA and enzymatic activities.
• TER stimulated CAR+A mutant nuclear translocation, but neither drug activated the CAR LBD or CAR3 variant.
• TER increased CAR mRNA expression, potentially via EGF receptor/ELK-1 inhibition or glucocorticoid receptor (GR) activation.

Conclusions:

• Teriflunomide (TER) is identified as a novel, indirect activator of the constitutive androstane receptor (CAR).
• TER's mechanism involves EGF receptor inhibition and glucocorticoid receptor (GR) activation.
• This pathway influences the expression of detoxification and intermediary metabolism genes.