title: Differential activation of human constitutive androstane receptor and its SV23 and SV24 splice variants by rilpivirine and etravirine.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Devinder
authors.initials: D
authors.lastname: Sharma
authors.forename: Aik Jiang
authors.initials: AJ
authors.lastname: Lau
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sherman
authors.forename: Thomas K H
authors.initials: TK
authors.lastname: Chang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics*; D000090702:Constitutive Androstane Receptor; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009570:Nitriles; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics* / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000068696:Rilpivirine / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000090702:Constitutive Androstane Receptor; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D000068696:Rilpivirine