Differential activation of human constitutive androstane receptor and its SV23 and SV24 splice variants by rilpivirine and etravirine.

Abstract

BACKGROUND AND PURPOSE:

Rilpivirine and etravirine are second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) indicated for the treatment of HIV/AIDS. The constitutive androstane receptor (CAR) regulates the expression of genes involved in various biological processes, including the transport and biotransformation of drugs. We investigated the effect of rilpivirine and etravirine on the activity of the wild-type human CAR (hCAR-WT) and its hCAR-SV23 and hCAR-SV24 splice variants, and compared it with first-generation NNRTIs (efavirenz, nevirapine, and delavirdine).

EXPERIMENTAL APPROACH:

Receptor activation, ligand-binding domain (LBD) transactivation, and co-activator recruitment were investigated in transiently transfected, NNRTI-treated HepG2 cells. Nuclear translocation of green fluorescent protein-tagged hCAR-WT and CYP2B6 gene expression were assessed in NNRTI-treated human hepatocytes.

KEY RESULTS:

Rilpivirine and etravirine activated hCAR-WT, but not hCAR-SV23 or hCAR-SV24, and without transactivating the LBD or recruiting steroid receptor coactivators SRC-1, SRC-2, or SRC-3. Among the first-generation NNRTIs investigated, only efavirenz activated hCAR-WT, hCAR-SV23, and hCAR-SV24, but none of them transactivated the LBD of these receptors or substantively recruited SRC-1, SRC-2, or SRC-3. Rilpivirine, etravirine, and efavirenz triggered nuclear translocation of hCAR-WT and increased hCAR target gene (CYP2B6) expression.

CONCLUSION AND IMPLICATIONS:

NNRTIs activate hCAR-WT, hCAR-SV23, and hCAR-SV24 in a drug-specific and isoform-selective manner. The activation occurs by a mechanism that does not appear to involve binding to the LBD or recruitment of SRC-1, SRC-2, or SRC-3.

• Authors: Devinder Sharma, Aik Jiang Lau, Matthew A Sherman, Thomas K H Chang
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 172 Issue 5 Pg. 1263-76 (Mar 2015) ISSN: 1476-5381 [Electronic] England
• PMID: 25363652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The British Pharmacological Society.

Chemical References

• Constitutive Androstane Receptor
• Nitriles
• Pyridazines
• Pyrimidines
• Receptors, Cytoplasmic and Nuclear
• Reverse Transcriptase Inhibitors
• etravirine
• CYP2B6 protein, human
• Cytochrome P-450 CYP2B6
• Rilpivirine

Topics

• Adolescent
• Adult
• Aged
• Alternative Splicing (drug effects, genetics)
• Constitutive Androstane Receptor
• Cytochrome P-450 CYP2B6 (genetics, metabolism)
• Dose-Response Relationship, Drug
• Female
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism)
• Humans
• Male
• Molecular Structure
• Nitriles
• Pyridazines (chemistry, pharmacology)
• Pyrimidines
• Receptors, Cytoplasmic and Nuclear (agonists, genetics, metabolism)
• Reverse Transcriptase Inhibitors (chemistry, pharmacology)
• Rilpivirine (chemistry, pharmacology)
• Structure-Activity Relationship
• Tumor Cells, Cultured
• Young Adult