Abstract
Detailed dose-response data recently archived by the National Center for Biotechnology Information (NCBI) identified 853 human CAR (hCAR) agonists by quantitative high-throughput screening (qHTS) assays applied to >9,000 chemicals tested at ≥14 concentrations using n = 3–48 replicates. By re-examining NCBI data on 746 agonists with replicate data sets each satisfying additional quality criteria, ∼95% had average values of agonist-specific Hill-model slopes estimated by NCBI that exceed 1 (i.e., exhibited an overall sublinear low-dose dose-response), and two unambiguously biphasic hCAR inhibitor-agonists were identified, 4-aminoazobenzene (n = 37) and ortho-aminoazotoluene (n = 3), both of which also cause rodent liver tumors. Although evidently rare among hCAR agonists, such biphasic responses add to evidence that nuclear receptors can exhibit complex patterns of low-dose response, consistent with previous observations and theoretical predictions for endpoints governed by ultrasensitive molecular switches. The pronounced biphasic hCAR response pattern observed for 4-aminoazobenzene is particularly noteworthy insofar as it was identified with statistical power that exceeds that of most if not all other receptor-mediated biphasic cellular responses to any single-chemical exposure reported to date.
Highlights
The constitutive androstane receptor (CAR, NR1I3) is a moderately promiscuous nuclear receptor and xenosensor expressed primarily in hepatocytes
The present study examined detailed activation data for 853 human CAR (hCAR) agonists identified from a total of >9,000 chemicals screened using a quantitative high-throughput screening luciferase reporter assay—recently archived by the National Center for Biotechnology Information (NCBI) [49]— to determine if responses exhibited by those identified CAR agonists include any clearly biphasic patterns
Of the 853 hCAR agonists identified by NCBI [49], 746 were determined to meet the additional criteria for unambiguous dose-response characterization described in Materials and Methods. doi:10.11131/2018/101321
Summary
The constitutive androstane receptor (CAR, NR1I3) is a moderately promiscuous nuclear receptor and xenosensor expressed primarily in hepatocytes. Phosphorylated and complexed with heat shock protein 90 (HSP90) and cytosolic CAR retention protein (CCRP) in cytosol, CAR can become activated, e.g., in mice by binding to a ligand, such as 1,4-bis[2(3,5- dichloropyridyloxy)]benzene (TCPOBOP), or in mice or humans by being dephosphorylated via phenobarbital-mediated recruitment of protein phosphatase 2 (PP2A), after which CAR translocates to the nucleus where it heterodimerizes with nuclear receptor RXR and interacts with promoter complexes of target genes that regulate many physiological processes including lipid metabolism, glucose metabolism, hormonal regulation, cell growth, wound healing, and apoptosis [1,2,3,4,5,6,7]. CAR antagonists or inverse agonists reported to attenuate and/or inhibit basal levels of CAR activity include: the mCAR inhibitors endogenous androstanol and the pheromone androstenol; the peripheral benzodiazepine receptor ligand PK11195, which activates human CAR (hCAR) in human cell lines; the potent agonist of liver X receptor (LXR) and the human pregnane X receptor (hPXR) TO901317, which inhibits human, mouse, and rat CAR; the soybean and legume phytoestrogen coumestrol, which inhibits hCAR; the antifungal agent ketoconazole, which inhibits hCAR and mCAR; and the hCAR-inhibiting type II diabetes drug metformin [32]
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