Last update 01 Nov 2024

CYP2B6 x NR1I3

Last update 01 Nov 2024

Basic Info

Related Targets

CYP2B6NR1I3

Drugs associated with CYP2B6 x NR1I3

DL-5055

Target

CYP2B6 x NR1I3

Mechanism

CYP2B6 agonists [+1]

Active Org.

University of Maryland

Originator Org.

University of Maryland

Active Indication

Non-Hodgkin Lymphoma [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CYP2B6 x NR1I3

100 Translational Medicine associated with CYP2B6 x NR1I3

0 Patents (Medical) associated with CYP2B6 x NR1I3

192

Literatures (Medical) associated with CYP2B6 x NR1I3

01 Dec 2024·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

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

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.

23 Apr 2024·Environmental Science & Technology

Filling the Blank Space: Branched 4-Nonylphenol Isomers Are Responsible for Robust Constitutive Androstane Receptor (CAR) Activation by Nonylphenol

Article

Author: Pavek, Petr ; Dušek, Jan ; Honkakoski, Paavo ; Kronenberger, Thales ; Poso, Antti ; Braeuning, Albert ; Smutná, Lucie ; Pijnenburg, Dirk ; Fritsche, Kristin ; Drastik, Martin ; Rashidian, Azam ; van Beuningen, Rinie

4-Nonylphenol (4-NP), a para-substituted phenolic compound with a straight or branched carbon chain, is a ubiquitous environmental pollutant and food contaminant. 4-NP, particularly the branched form, has been identified as an endocrine disruptor (ED) with potent activities on estrogen receptors. Constitutive Androstane Receptor (CAR) is another crucial nuclear receptor that regulates hepatic lipid, glucose, and steroid metabolism and is involved in the ED mechanism of action. An NP mixture has been described as an extremely potent activator of both human and rodent CAR. However, detailed mechanistic aspects of CAR activation by 4-NP are enigmatic, and it is not known if 4-NP can directly interact with the CAR ligand binding domain (LBD). Here, we examined interactions of individual branched (22NP, 33NP, and 353NP) and linear 4-NPs with CAR variants using molecular dynamics (MD) simulations, cellular experiments with various CAR expression constructs, recombinant CAR LBD in a TR-FRET assay, or a differentiated HepaRG hepatocyte cellular model. Our results demonstrate that branched 4-NPs display more stable poses to activate both wild-type CAR1 and CAR3 variant LBDs in MD simulations. Consistently, branched 4-NPs activated CAR3 and CAR1 LBD more efficiently than linear 4-NP. Furthermore, in HepaRG cells, we observed that all 4-NPs upregulated CYP2B6 mRNA, a relevant hallmark for CAR activation. This is the first study to provide detailed insights into the direct interaction between individual 4-NPs and human CAR-LBD, as well as its dominant variant CAR3. The work could contribute to the safer use of individual 4-NPs in many areas of industry.

01 Dec 2023·Toxicology and Applied Pharmacology

Genetic polymorphisms of CYP2B6 is a risk of metabolic associated fatty liver disease in Chinese population

Article

Author: Kang, Yuwei ; Zhou, Wei ; Zhang, Jingwei ; Ma, Shijie ; Yang, Wei ; Zhang, Heping ; Feng, Jing ; Deng, Fei

BACKGROUNDThe expression and activity of cytochrome P450 2B6 (CYP2B6) may be related to the metabolic associated fat liver disease (MAFLD). Since constitutive androstane receptor (CAR) is a classic transcriptional regulator of CYP2B6, and the single nucleotide polymorphisms (SNPs) of CYP2B6 and CAR are both associated with adverse reactions of efavirenz, we hypothesized that genetic polymorphisms of CAR might also result in additional interindividual variability in CYP2B6. This study was devoted to explore the association between CYP2B6 and CAR SNPs and susceptibility to MAFLD.MATERIALS AND METHODSA total of 590 objects of study (118 with MAFLD and 472 healthy control) between December 2014 and April 2018 were retrospectively enrolled. Twenty-two selected SNPs in CYP2B6 and CAR were genotyped with a custom-designed 48-plex SNP Scan TM® Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between the two groups. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated.RESULTSThe T allele of rs3745274 in CYP2B6 was associated with a decreased risk for MAFLD (OR 0.610; 95% CI: 0.451-0.825, p = 0.001) which was still statistically significant after adjusting with Bonferroni method(p = 0.014) The allele, genotype and genetic model frequencies were similar in the two groups for the other twenty-one SNPs (all P > 0.05). There were no multiplicative or additive interactions between the SNPs.CONCLUSIONOur study revealed that rs3745274 variants in CYP2B6 is associated with susceptibility to MAFLD in the Han Chinese population.

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