Small-molecule modulators of PXR and CAR

Chai, Sergio C.; Cherian, Milu T.; Wang, Yueming; Chen, Taosheng

doi:10.1016/j.bbagrm.2016.02.013

Cited by 66 publications

(75 citation statements)

References 158 publications

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“…Activation of PPARα by its natural ligands (FFAs) increases the expression of genes encoding enzymes involved in FFA oxidation (such as CPT1 and ACOX1 ) and hence leads to decreased hepatic steatosis 54 . Similarly, xenobiotics bind and activate CAR and PXR; however, species-specific differences clearly exist 55, 56 . For example, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) activates the mouse but not the human CAR 57,58 , while 6-(4-chlorophenyl)imidazo[2,1- b ][1,3]thiazole-5-carbaldehyde O -(3,4-dichlorobenzyl)oxime (CITCO) activates the human, but not mouse, CAR 55, 56, 59 .…”

Section: Liver Fat Metabolism and Edcsmentioning

confidence: 99%

Endocrine-disrupting chemicals and fatty liver disease

et al. 2017

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Nonalcoholic fatty liver disease (NAFLD) is a growing epidemic paralleling the increase in obesity and diabetes mellitus seen in Western diet-consuming countries. As NAFLD can lead to life-threatening conditions such as cirrhosis and hepatocellular carcinoma (HCC), an understanding of factors that trigger its development and pathological progression is needed. Although by definition this disease is not associated with alcohol consumption, exposure to environmental agents that have been linked to other diseases might have a role in the development of NAFLD. Here, we focus on one class of these agents, endocrine-disrupting chemicals (EDCs), and their potential to influence the initiation and progression of a cascade of pathological conditions associated with fatty liver. Experimental studies have revealed several potential mechanisms by which EDC exposures might contribute to disease pathogenesis, including modulation of nuclear hormone receptor (NR) function and alteration of the epigenome. However, many questions remain to be addressed about the causal link between acute and chronic EDC exposure and the development of NAFLD in humans. Future studies that address these questions hold promise not only for understanding the linkage between EDC exposure and liver disease, but for elucidating the molecular mechanisms underpinning NAFLD and the development of new prevention and treatment opportunities.

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Section: Liver Fat Metabolism and Edcsmentioning

confidence: 99%

Endocrine-disrupting chemicals and fatty liver disease

et al. 2017

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“…Therefore, a contextual relevance of these interactions remains at play in any given tumor type (Robbins et al, 2016). PXR has been proposed as a therapeutic target in treating several human diseases including cancer (Banerjee et al, 2014; Cecchin et al, 2016; Chai et al, 2016; Chen, 2008, 2010; Gao and Xie, 2012; Mani et al, 2013; Pondugula and Mani, 2013). Depending on the cancer tissue or cellular context, PXR activation or inhibition has been shown to exert anticancer phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Pregnane X Receptor and Cancer: Context-Specificity is Key

Pondugula

Pávek

Mani

2016

Nuclear Receptor Research

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Pregnane X receptor (PXR) is an adopted orphan nuclear receptor that is activated by a wide-range of endobiotics and xenobiotics, including chemotherapy drugs. PXR plays a major role in the metabolism and clearance of xenobiotics and endobiotics in liver and intestine via induction of drug-metabolizing enzymes and drug-transporting proteins. However, PXR is expressed in several cancer tissues and the accumulating evidence strongly points to the differential role of PXR in cancer growth and progression as well as in chemotherapy outcome. In cancer cells, besides regulating the gene expression of enzymes and proteins involved in drug metabolism and transport, PXR also regulates other genes involved in proliferation, metastasis, apoptosis, anti-apoptosis, inflammation, and oxidative stress. In this review, we focus on the differential role of PXR in a variety of cancers, including prostate, breast, ovarian, endometrial, and colon. We also discuss the future directions to further understand the differential role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators to target PXR in PXR-expressing cancers.

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“…PXR is an orphan nuclear receptor (NR), mainly synthesized in the liver and intestine, and has a highly flexible and hydrophobic ligand-binding domain, which enables it to bind a vast array of structurally diverse molecules [91–94]. PXR is activated by agonist binding.…”

Section: Expression and Enzymatic Activities Of Cyp3a4 And Cyp3a5mentioning

confidence: 99%

“…Although CAR shares substantial structural and functional similarities with PXR, it binds far less chemical entities than PXR, partly because of its smaller ligand-binding pocket [94,111–114]. It exerts transcriptional control on its target genes in a similar way to PXR.…”

Section: Expression and Enzymatic Activities Of Cyp3a4 And Cyp3a5mentioning

confidence: 99%

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

Lolodi

Wang

Wright

et al. 2018

CDM

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Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body’s natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR) and the cytochrome P450 (CYP) 3A4 and 3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them.

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Small-molecule modulators of PXR and CAR

Cited by 66 publications

References 158 publications

Endocrine-disrupting chemicals and fatty liver disease

Endocrine-disrupting chemicals and fatty liver disease

Pregnane X Receptor and Cancer: Context-Specificity is Key

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

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