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-(3,4-dichlorobenzyl)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 noncanonical 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 5'-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 UDP-glucuronosyltransferase 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 5'-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.

Bile acid; Chromatin; Constitutive androstane receptor; Drug metabolism; SWI/SNF complex.