Use of comprehensive screening methods to detect selective human CAR activators

The so-called human xenosensors, constitutive androstane receptor (hCAR), pregnane X receptor (hPXR) and aryl hydrocarbon receptor (hAhR), participate in drug metabolism and transport as well as in several endogenous processes by regulating the expression of their target genes. Here, validated reporter assays for these three xenosensors are presented and thereafter used to screen a large set of chemicals to find novel selective hCAR ligands. The authors introduce a novel selective hCAR agonist, FL81, which can be used as a stable positive control in hCAR activity assays. The authors’ established receptor-selective ligand identification methods consisting of supporting biological assays and molecular modelling techniques are then used to study FL81 as well as other discovered ligands, such as diethylstilbestrol, o,p’-DDT, methoxychlor and permethrin, for their ability to specifically activate hCAR and to regulate the CYP enzyme expression and function.

Authors: Kueblbeck, Jenni; Laitinen, Tuomo; Jyrkkaerinne, Johanna; Rousu, Timo; Tolonen, Ari; Abel, Tobias; Kortelainen, Tanja; Uusitalo, Jouko; Korjamo, Timo; Honkakoski, Paavo; Molnar, Ferdinand ;Full Source: Biochemical Pharmacology [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][online computer file] 2011, 82(12), 1994-2007 (Eng) ;