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Differential activation of human constitutive androstane receptor and its SV23 and SV24 splice variants by rilpivirine and etravirine
Author(s) -
Sharma Devinder,
Lau Aik Jiang,
Sherman Matthew A,
Chang Thomas K H
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12997
Subject(s) - etravirine , rilpivirine , constitutive androstane receptor , transactivation , efavirenz , chemistry , pharmacology , nevirapine , biology , nuclear receptor , gene expression , biochemistry , reverse transcriptase , virology , gene , transcription factor , human immunodeficiency virus (hiv) , rna , antiretroviral therapy , viral load
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 NNRTI s (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.