PXR as the tipping point between innate immune response, microbial infections, and drug metabolism

Bautista-Olivier, Carlos Daniel; Elizondo, Guillermo

doi:10.1016/j.bcp.2022.115147

Cited by 15 publications

(10 citation statements)

References 110 publications

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“…In this context, epithelial NF-κB signaling is thought to be essential for the maintenance of epithelial self-renewal and the maintenance of a proper balance between Paneth and goblet cells (Brischetto, Krieger et al 2021). In our context, however, PXR inhibits NF-κB signaling (Shah, Ma et al 2007, Bautista-Olivier andElizondo 2022), creating an apparent contradiction. However, it is known that noncanonical epithelial NF-κB via the supplementation of RelA dimers to the canonical NF-κB modules exacerbates intestinal inflammation (McDaniel, Eden et al 2016, Ke, Chen et al 2019, Ramakrishnan, Zhang et al 2019, Chawla, Mukherjee et al 2021).…”

Section: Brief Historical Perspectivementioning

confidence: 67%

Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

Dvořák

Mani

2022

Drug Metab Dispos

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Xenobiotic receptors, for example like the pregnane X receptor, regulate multiple host physiological pathways including xenobiotic metabolism, certain aspects of cellular metabolism, and innate immunity. These ligand-dependent nuclear factors regulate gene expression via genomic recognition of specific promoters and transcriptional activation of the gene. Natural or endogenous ligands are not commonly associated with this class of receptors; however, since these receptors are expressed in a cell-type specific manner in the liver and intestines, there has been significant recent effort to characterize microbially derived metabolites as ligands for these receptors. In general, these metabolites are thought to be weak micromolar affinity ligands. This journal anniversary minireview will focus on recent efforts to derive potentially non-toxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic-receptor modifying pathophysiology. The review will include our perspective of the field and recommend certain directions for future research. SIGNIFICANCE STATEMENTThe xenobiotic receptors (XR) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors, but also to respond to the complex metabolic environment present in the intestines. Specifically, this review focuses on describing microbial metabolite-XR interactions and the translation of these findings towards discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.

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Section: Brief Historical Perspectivementioning

confidence: 67%

Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

Dvořák

Mani

2022

Drug Metab Dispos

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“…Zdeněk Dvořák 1,3,4,5,7,8,9,11,12,13 , Barbora Vyhlídalová 3,7,11 , Petra Pečinková 2,3,5 , Hao Li 2,3,5 , Pavel Anzenbacher 2,3,5,6,9,10,11 , Alena Špičáková 2,3,5,6 , Eva Anzenbacherová 2,3,5,6 , Vimanda Chow 2,3,5,6,10,11 , Jiabao Liu 2,3,5,6,10,11 , Henry Krause 2,3,5,6,10,11 , Derek Wilson 2,3,5,6,10,11 , Tibor Berés 2,3,5,6,10,11 , Petr Tarkowski 2,…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…Therefore, drug discovery suspended the substances that activated PXR from further testing. However, more recently, multiple physiological roles of PXR have been unveiled, including regulating inappropriate inflammation in various organs like the gastrointestinal tract (e.g., inflammatory bowel disease; IBD) [1][2][3][4][5][6]. Since the initial discovery of the PXR and its functional importance as a master regulator of the drug metabolism [7], a new pharmacotherapeutic paradigm might be important in that, for specific diseases (e.g., IBD), dialing-in PXR activity, especially in the intestines and not systemically, could safely expand the new drug space [8,9].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Safety Signals for Potential Clinical Development of the Anti-Inflammatory Pregnane X Receptor Agonist FKK6

Dvořák,

Vyhlídalová,

Pečinková

et al. 2023

Preprint

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Background and purpose: Based on the mimicry of microbial metabolites, functionalized indoles were demonstrated as the ligands and agonists of the pregnane xenobiotic receptor. The lead indole, FKK6, displayed pregnane xenobiotic receptor-dependent protective effects in DSS induced colitis in mice and in vitro cytokine-treated intestinal organoid cultures. Here, we performed the initial in vitro pharmacological profiling of FKK6. Experimental approach: A complex series of cell-free and cell-based assays were employed. The organic synthesis, and advanced analytical chemistry methods were used. Key results: FKK6-pregnane xenobiotic receptor interactions were characterized by hydrogen-deuterium exchange mass spectrometry. Screening FKK6 against potential cellular off-targets revealed high pregnane xenobiotic receptor selectivity. FKK6 has poor aqueous solubility but was highly soluble in simulated gastric and intestinal fluids. FKK6 was bound to plasma proteins and chemically stable in plasma. The partition coefficient of FKK6 was 2.70, and FKK6 moderately partitioned into red blood cells. In Caco2 cells, FKK6 displayed high permeability (A-B: 22.8 times 10-6 cm.s-1) and no active efflux. These data are indicative of essentially complete in vivo absorption of FKK6. FKK6 was rapidly metabolized by cytochromes P450, notably by CYP3A4 in human liver microsomes. Two oxidized FKK6 derivatives, including N6 oxide and C19-phenol, were detected, and these metabolites had 5-7 times lower potency as pregnane xenobiotic receptor agonists than FKK6. This implies that despite high intestinal absorption, FKK6 is rapidly eliminated by the liver, and its pregnane xenobiotic receptor effects are predicted to be predominantly in the intestines. Conclusion and implications: The pregnane xenobiotic receptor ligand and agonist FKK6 has a suitable pharmacological profile supporting its potential preclinical development.

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“…These are recognized by Toll-like receptors (TLRs), further amplifying the inflammatory response to the extent that it causes autoreactivity. Although the exact mechanisms of autoimmunity by xenobiotic exposure are still unknown, recent studies link a Pregnane X receptor (PXR) as a xenosensor that links toxic insults to PXR and nuclear factor-kappa B (NF-kB), Toll-like receptors (TLRs), and inflammasome components [ 28 ]. Further, NLRP3a-mediated inflammasomes are T regulatory cells also involved in heavy metals or drugs related to immunotoxicity and autoimmunity.…”

Section: Immunotoxicity Of Xenobiotics: Exposure Routes Signaling Pat...mentioning

confidence: 99%

Immunomodulation, Toxicity, and Therapeutic Potential of Nanoparticles

Pandey

Mishra

2022

BioTech

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Altered immune responses associated with human disease conditions, such as inflammatory and infectious diseases, cancers, and autoimmune diseases, are among the primary causes of morbidity across the world. A wealth of studies has demonstrated the efficiency of nanoparticles (NPs)-based immunotherapy strategies in different laboratory model systems. Nanoscale dimensions (<100 nm) enable NPs to have increased surface area to volume ratio, surface charge, and reactivity. Physicochemical properties along with the shapes, sizes, and elasticity influence the immunomodulatory response induced by NPs. In recent years, NPs-based immunotherapy strategies have attained significant focus in the context of cancers and autoimmune diseases. This rapidly growing field of nanomedicine has already introduced ~50 nanotherapeutics in clinical practices. Parallel to wide industrial applications of NPs, studies have raised concerns about their potential threat to the environment and human health. In past decades, a wealth of in vivo and in vitro studies has demonstrated the immunotoxicity potential of various NPs. Given that the number of engineered/designed NPs in biomedical applications is continuing to increase, it is pertinent to establish the toxicity profile for their safe and intelligent use in biomedical applications. The review is intended to summarize the NPs-induced immunomodulation pertaining to toxicity and therapeutic development in human health.

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PXR as the tipping point between innate immune response, microbial infections, and drug metabolism

Cited by 15 publications

References 110 publications

Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future

In Vitro Safety Signals for Potential Clinical Development of the Anti-Inflammatory Pregnane X Receptor Agonist FKK6

Immunomodulation, Toxicity, and Therapeutic Potential of Nanoparticles

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