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更新于：2025-05-07

NR1I3 x CYP2B6

更新于：2025-05-07

基本信息

关联

项与 NR1I3 x CYP2B6 相关的药物

DL-5055

靶点

CYP2B6 x NR1I3

作用机制

CYP2B6 agonists [+1]

在研机构

University of Maryland

原研机构

University of Maryland

在研适应症

非霍奇金淋巴瘤 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 NR1I3 x CYP2B6 相关的临床结果

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100 项与 NR1I3 x CYP2B6 相关的转化医学

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0 项与 NR1I3 x CYP2B6 相关的专利（医药）

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234

项与 NR1I3 x CYP2B6 相关的文献（医药）

2025-06-01·Environmental Toxicology and Pharmacology

Comparison of the impact of chlordecone and its metabolite chlordecol on genes involved in pesticide metabolism in HepG2 cell line

Article

作者: Joubert, Olivier ; Djansugurova, Leyla ; El Sheikh Saad, Hanan ; Paul, Arnaud ; Cakir-Kiefer, Céline ; Huguet, Marion ; Fournier, Agnès ; Baratzhanova, Gulminyam

Chlordecone (CLD) is an organochlorine pesticide that is highly resistant in the environment. This compound and its metabolite chlordecol (CLD-OH) still can be found in the French West Indies, after being banned 30 years ago. The novelty of this work lies in evaluating the toxicity of CLD-OH compared to CLD and examining the effects of these compounds on nuclear receptor (PXR, PPARα, and CAR) and metabolism-related genes (CYP2B6, CYP3A4) in vitro using HepG2 cell line as a model. Our study demonstrates that both compounds displayed an almost similar pattern of decrease in cell viability. Moreover, it was shown that CLD-OH can increase the expression of PXR, CYP3A4, and PPARα genes in comparison to CLD. The AKR1C4 gene showed a slight decrease in expression after CLD treatment. Collectively, this study provided a new finding into the impact of CLD-OH and compares the mode of action of CLD and its metabolite.

2025-04-01·Drug Metabolism and Disposition

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

Article

作者: Fukami, Tatsuki ; Yokoseki, Itsuki ; Tomii, Mei ; Higuchi, Yuichiro ; Suemizu, Hiroshi ; Nakajima, Miki ; Yoneda, Nao ; Kurosawa, Kiamu ; Uehara, Shotaro ; Nakano, Masataka

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.

2024-12-01·Toxicology in Vitro

Effects of di-(2-ethylhexyl) phthalate and its metabolites on transcriptional activity via human nuclear receptors and gene expression in HepaRG cells

Article

作者: Hakota, Ryo ; Uramaru, Naoto ; Yasuda, Ayaka ; Ikeda, Atsuko ; Kubota, Atsuhito ; Murase, Wataru ; Kojima, Hiroyuki ; Okuda, Katsuhiro

Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in polyvinyl chloride products. DEHP exposure in humans is of great concern due to its endocrine-disrupting properties. In this study, we characterized the agonistic activities of DEHP and its five metabolites, mono-(2-ethylhexyl) phthalate (MEHP), 5OH-MEHP, 5oxo-MEHP, 5cx-MEPP and 2cx-MMHP against human nuclear receptors, peroxisome proliferator-activated receptor α (PPARα), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) using transactivation assays. In the PPARα assay, the order of the agonistic activity was MEHP >> 5cx-MEPP >5OH-MEHP, 5oxo-MEHP >2cx-MMHP > DEHP, with DEHP significantly inhibiting MEHP-induced PPARα agonistic activity. This finding was compared to the results from in silico docking simulation. In the PXR assay, DEHP showed PXR agonistic activity more potent than that of MEHP, whereas the other metabolites showed little activity. In the CAR assay, none of the tested compounds showed agonistic activity. Moreover, the expression levels of PPARα-, PXR-, and CAR-target genes in HepaRG cells exposed to DEHP or MEHP were investigated using qRT-PCR analysis. As a result, exposure to these compounds significantly upregulated PXR/CAR target genes (CYP3A4 and CYP2B6), but not PPARα target genes (CYP4A11, etc.) in HepaRG cells. Taken together, these results suggest that direct PXR and/or indirect CAR activation by several DEHP metabolites may be involved in the endocrine disruption by altering hormone metabolism.

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