Switch/sucrose non-fermentable complex interacts with constitutive androstane receptor to regulate drug-metabolizing enzymes and transporters in the liver

Constitutive androstane receptor (CAR) is a nuclear receptor that plays an important role in regulating drug metabolism and bile acid homeostasis in the liver. Recently, it was revealed that the switch/sucrose non-fermentable (SWI/SNF) complex, a chromatin remodeler, regulates transactivation by nuclear receptors, such as the pregnane X receptor and vitamin D receptor. However, studies on the involvement of the SWI/SNF complex in CAR-mediated transactivation are limited. Here, we demonstrated that the induction of cytochrome P450 CYP2B6 expression by CAR activators, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4dichlorobenzyl)oxime and phenobarbital, was enhanced by the inhibition of AT-rich interactive domain-containing protein (ARID) 1A, a canonical brahma-related gene 1-associated factor (cBAF) component, one of the SWI/SNF complexes, and was attenuated by inhibition of bromodomain-containing protein (BRD) 9, a non-canonical BAF(ncBAF) component, in primary hepatocytes from humanized mice. Coimmunoprecipitation assays revealed that ARID1A and BRD9 interacted with CAR. Chromatin immunoprecipitation assay revealed that the 6(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime-induced binding of CAR to the 50-flanking region of CYP2B6 gene increased with ARID1A inhibition and reduced with BRD9 inhibition. These results suggest that cBAF negatively regulates CAR-mediated transactivation by attenuating CAR binding to its response element, whereas ncBAF positively regulates it by facilitating CAR binding. Furthermore, ARID1A inhibition enhanced phenobarbital-induced increases in UDP-glucuronosyltransferase 1A1 expression and multidrug resistance-associated protein 2 mRNA level and activity. Collectively, our findings indicate that cBAF and ncBAF play essential roles in xenobiotic metabolism by regulating CAR-mediated transactivation and that ARID1A inhibitors may offer therapeutic benefits for hyperbilirubinemia and cholestasis by inducing UDPglucuronosyltransferase 1A1 and multidrug resistance-associated protein 2 expression. Significance Statement: This study revealed that canonical brahma-related gene 1-associated factor and noncanonical brahma-related gene 1-associated factor, members of the switch/sucrose non-fermentable family, negatively and positively regulate constitutive androstane receptor (CAR) transactivation, respectively, through changes in the chromatin structure around the CAR response element in the 50-flanking regions of CAR target genes. The inhibition of AT-rich interactive domain-containing protein 1A may be beneficial for cholestasis treatment by enhancing CAR-mediated transactivation. (c) 2025 The Author(s). Published by Elsevier Inc. on behalf of American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).