Xenobiotic Receptor Research Articles

Investigating the effects of long-term Aroclor 1260 exposure on fatty liver disease in a diet-induced obesity mouse model.

Polychlorinated biphenyls (PCBs) are persistent environmental toxicants that have been implicated in numerous health disorders including liver diseases such as non-alcoholic fatty liver disease (NAFLD). Toxicant-associated NAFLD, also known as toxicant-associated fatty liver disease (TAFLD), consists of a spectrum of disorders ranging from steatosis and steatohepatitis to fibrosis and hepatocellular carcinoma. Previously, our group demonstrated that 12-week exposure to the PCB mixture, Aroclor 1260, exacerbated steatohepatitis in high-fat diet (HFD)-fed mice; however, the longer-term effects of PCBs on TAFLD remain to be elucidated. This study aims to examine the longer-term effects of Aroclor 1260 (>30 weeks) in a diet-induced obesity model to better understand how duration of exposure can impact TAFLD. Male C57BL/6 mice were exposed to Aroclor 1260 (20 mg/kg) or vehicle control by oral gavage at the beginning of the study period and fed either a low-fat diet (LFD) or HFD throughout the study period. Aroclor 1260 exposure (>30 weeks) led to steatohepatitis only in LFD-fed mice. Several Aroclor 1260 exposed LFD-fed mice also developed hepatocellular carcinoma (25%), which was absent in HFD-fed mice. The LFD+Aroclor1260 group also exhibited decreased hepatic Cyp7a1 expression and increased pro-fibrotic Acta2 expression. In contrast, longer term Aroclor 1260 exposure in conjunction with HFD did not exacerbate steatosis or inflammatory responses beyond those observed with HFD alone. Further, hepatic xenobiotic receptor activation by Aroclor 1260 was absent at 31 weeks post exposure, suggesting PCB redistribution to the adipose and other extra-hepatic tissues with time. Overall, the results demonstrated that longer-term PCB exposure worsened TAFLD outcomes independent of HFD feeding and suggests altered energy metabolism as a potential mechanism fueling PCB mediated toxicity without dietary insult. Additional research exploring mechanisms for these longer-term PCB mediated toxicity in TAFLD is warranted.

Resveratrol protects against cadmium-induced cerebrum toxicity through modifications of the cytochrome P450 enzyme system in microsomes.

Cadmium (Cd), known as a vital contaminant in the environment, penetrates the blood-brain barrier and accumulates in the cerebrum. Acute toxicosis of Cd, which leads to lethal brain cerebral edema, intracellular accumulation and cellular dysfunction, remains to be illuminated with regard to the exact molecular mechanism of cerebral toxicity. Resveratrol (RES) existing in the edible portions of numerous plants is a simply acquirable and correspondingly less toxic natural compound with neuroprotective potential, which provides some theoretical bases for antagonizing Cd-induced cerebral toxicity. This work was executed to research the protective effects of RES against Cd-induced toxicity in chicken cerebrum. Markedly, these lesions were increased in the Cd group, which also exhibited a thinner cortex, reduced granule cells, vacuolar degeneration, and an enlarged medullary space in the cerebrum. Furthermore, Cd induced CYP450 enzyme metabolism disorders by interfering the nuclear xenobiotic receptor response (NXRs), enabling cerebrum to reduce the ability to metabolize exogenous substances, eventually leading to Cd accumulation. Meanwhile, accumulated Cd promotes the oxidative damage, and synergistically promote the damage of the neurons and glial cells. RES initiated the NXRs (especially for AHR and PXR), decreasing the expression of CYP450 genes, changing the content of CYP450, maintaining CYP450 enzyme normal activities, and exerting antagonistic action against the Cd-induced abnormal response of nuclear receptors. These results suggested that the cerebrum toxicity caused by Cd was reduced by pretreatment with RES. This article is protected by copyright. All rights reserved.

In vitro and in silico assessment of endocrine disrupting effects of food contaminants through pregnane X receptor.

As a promiscuous xenobiotic receptor, pregnane X receptor (PXR) has been confirmed to participate in numerous physiological process. In addition to the conventional estrogen/androgen receptor, PXR also serves as an alternative target for environmental chemical contaminants. In this work, the PXR-mediated endocrine disrupting effects of typical food contaminants were explored. Firstly, the time-resolved fluorescence resonance energy transfer assays confirmed the PXR binding affinities of 2,2',4,4',5,5'-hexachlorobiphenyl, bis(2-ethylhexyl) phthalate, dibutyl phthalate, chlorpyrifos, bisphenol A, and zearalenone, with IC50 values ranging from 1.88 to 4284.00nM. Then their PXR agonist activities were assessed by PXR-mediated CYP3A4 reporter gene assays. Subsequently, the regulation of gene expressions of PXR and its targets CYP3A4, UGT1A1, and MDR1 by these compounds was further investigated. Intriguingly, all the tested compounds interfered with these gene expressions, confirming their endocrine disrupting effects via PXR-mediated signaling. The compound-PXR-LBD binding interactions were explored by molecular docking and molecular dynamics simulations to unravel the structural basis of their PXR binding capacities. The weak intermolecular interactions are key players in stabilizing these compound-PXR-LBD complexes. During the simulation process, 2,2',4,4',5,5'-hexachlorobiphenyl remained stable while the other 5 compounds underwent relatively severe disturbances. In conclusion, these food contaminants might exhibit endocrine disrupting effects via PXR.

Cognitive and hippocampal effects of adult male mice exposure to environmentally relevant doses of phthalates

We recently showed that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture altered blood brain barrier integrity and induced an inflammatory profile in the hippocampus. Here, we investigate whether such exposure alters hippocampus-dependent behavior and underlying cellular mechanisms. Adult C57BL/6 J male mice were continuously exposed orally to the vehicle or DEHP alone (5 or 50 μg/kg/d) or to DEHP (5 μg/kg/d) in a phthalate mixture. In the Morris water maze, males showed reduced latencies across days to find the platform in the cue and spatial reference memory tasks, regardless of their treatment group. In the probe test, DEHP-50 exposed males displayed a higher latency to find the platform quadrant. In the temporal order memory test, males exposed to DEHP alone or in a phthalate mixture were unable to discriminate between the most recently and previously seen objects. They also displayed reduced ability to show a preference for the new object in the novel object recognition test. These behavioral alterations were associated with a lowered dendritic spine density and protein levels of glutamate receptors and postsynaptic markers, and increased protein levels of the presynaptic synaptophysin in the hippocampus. Metabolomic analysis of the hippocampus indicated changes in amino acid levels including reduced tryptophan and L-kynurenine and elevated NAD + levels, respectively, a precursor, intermediate and endproduct of the kynurenine pathway of tryptophan metabolism. Interestingly, the protein amounts of the xenobiotic aryl hydrocarbon receptor, a target of this metabolic pathway, were elevated in the CA1 area. These data indicate that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture impacted hippocampal function and structure, associated with modifications in amino acid metabolites with a potential involvement of the kynurenine pathway of tryptophan metabolism.

PPARα Induces the Expression of CAR That Works as a Negative Regulator of PPARα Functions in Mouse Livers.

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that controls the transcription of genes responsible for fatty acid metabolism. We have recently reported a possible drug-drug interaction mechanism via the interaction of PPARα with the xenobiotic nuclear receptor constitutive androstane receptor (CAR). Drug-activated CAR competes with the transcriptional coactivator against PPARα and prevents PPARα-mediated lipid metabolism. In this study, to elucidate the crosstalk between CAR and PPARα, we focused on the influence of PPARα activation on CAR's gene expression and activation. Male C57BL/6N mice (8-12 weeks old, n = 4) were treated with PPARα and CAR activators (fenofibrate and phenobarbital, respectively), and hepatic mRNA levels were determined using quantitative reverse transcription PCR. Reporter assays using the mouse Car promoter were performed in HepG2 cells to determine the PPARα-dependent induction of CAR. CAR KO mice were treated with fenofibrate, and the hepatic mRNA levels of PPARα target genes were determined. Treatment of mice with a PPARα activator increased Car mRNA levels as well as genes related to fatty acid metabolism. In reporter assays, PPARα induced the promoter activity of the Car gene. Mutation of the putative PPARα-binding motif prevented PPARα-dependent induction of reporter activity. In electrophoresis mobility shift assay, PPARα bound to the DR1 motif of the Car promoter. Since CAR has been reported to attenuate PPARα-dependent transcription, CAR was considered a negative feedback protein for PPARα activation. Treatment with fenofibrate induced the mRNA levels of PPARα target genes in Car-null mice more than those in wild-type mice, suggesting that CAR functions as a negative feedback factor for PPARα.

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

In the above article [Dvořák Z, Li H, and Mani S (2023) Drug Metab Dispos, 51(2): [219-227][1], DOI: <https://doi.org/10.1124/dmd.122.000860>], was published with three errors introduced by the compositor during the proofing process. These errors do not affect the conclusions of the paper. The

Thyroid-on-a-Chip: An Organoid Platform for In Vitro Assessment of Endocrine Disruption.

Thyroid is a glandular tissue in the human body in which the function can be severely affected by endocrine disrupting chemicals (EDCs). Current in vitro assays to test endocrine disruption by chemical compounds are largely based on 2Dthyroid cell cultures, which often fail to precisely evaluate the safety of these compounds. New and more advanced 3Dcell culture systems are urgently needed to better recapitulate the thyroid follicular architecture and functions and help to improve the predictive power of such assays. Herein, the development of a thyroid organoid-on-a-chip (OoC) device using polymeric membranous carriers is described. Mouse embryonic stem cell derived thyroid follicles are incorporated in a microfluidic chip for a 4 day experiment at a flow rate of 12µL min-1 . A reversible seal provides a leak-tight sealing while enabling quick and easy loading/unloading of thyroid follicles. The OoC model shows a high degree of functionality, where organoids retain expression of key thyroid genes and a typical follicular structure. Finally, transcriptional changes following benzo[k]fluoranthene exposure in the OoC device demonstrate activation of the xenobiotic aryl hydrocarbon receptor pathway. Altogether, this OoC system is a physiologically relevant thyroid model, which will represent a valuable tool to test potential EDCs.

The Role of the Kynurenine/AhR Pathway in Diseases Related to Metabolism and Cancer.

The Aryl hydrocarbon receptor (AhR) is a xenobiotic and endobiotic receptor, which regulates many cellular processes from contaminant metabolism to immunomodulation. Consequently, it is also involved in pathophysiological pathways and now represents a potential therapeutical target. In this review, we will highlight the ancestral function of the protein together with an illustration of its ligand's battery, emphasizing the different responses triggered by these high diverse molecules. Among them, several members of the kynurenine pathway (one key process of tryptophan catabolism) are AhR agonists and are subsequently involved in regulatory functions. We will finally display the interplay between Tryptophan (Trp) catabolism and dysregulation in metabolic pathways drawing hypothesis on the involvement of the AhR pathway in these cancer-related processes.

Particulate matter 2.5 induces the skin barrier dysfunction and cutaneous inflammation via AhR- and T helper 17 cell-related genes in human skin tissue as identified via transcriptome analysis.

Particulate matter (PM2.5) is an environmental pollutant causing skin inflammatory diseases via epidermal barrier damage. However, the mechanism and related gene expression induced by PM2.5 remains unclear. Our aim was to determine the effect of PM2.5 on human skin tissue ex vivo, and elucidate the mechanism of T helper 17 cell-related inflammatory cytokine and skin barrier function. We verified the expression levels of gene in PM2.5-treated human skin tissue using Quantseq (3' mRNA-Seq), and Gene Ontology (GO) terms and protein-protein interaction (PPI) networks were performed. The PM2.5 treatment significantly enhanced the expression of Th 1, 2, 17 and 22 cell-related genes (cut-off value: │1.2 │ > fold change and p < 0.05). Most of all, Th17 cell-related genes are upregulated and those genes are associated with skin epidermal barrier function and Aryl hydrocarbon receptor (AhR), a xenobiotic receptor, pathway. In human keratinocyte cell lines, AhR-regulated genes (e.g. AhRR, CYP1A1, IL6 and IL36G), Th17 cell-related genes (e.g. IL17C) and epidermal barrier-related genes (e.g. SPRR2A and KRT71) are significantly increased after PM2.5. In the protein level, the secretion of IL-6 and IL-36G was increased in human skin tissue following PM2.5 treatment, and the expression of SPRR2A and KRT71 was significantly increased. PM2.5 exposure could ruin the skin epidermal barrier function via AhR- and Th17 cell-related inflammatory pathway.

Aspects of xenobiotics and their receptors in stroke

AbstractStroke is devastating and the second leading cause of disability and death worldwide. The pathophysiology of stroke is intricate involving oxidative stress, ionic imbalance, and excitotoxicity leading to cell death. The current therapeutic strategies for ischemic stroke primarily aim to restore cerebral blood flow by removing clots using intravenous thrombolysis and mechanical thrombectomy. However, hemorrhagic stroke requires different therapeutic interventions, where intravenous thrombolysis worsens the persistent condition. Nevertheless, the present treatment strategies do not provide effective neuroprotection as they have limitations such as narrow time window, specialized clinics and personnel, and higher expense. Therefore, studies on novel therapeutic strategies that can render neuroprotection over an extended time with minimum adverse effects are solicited. Xenobiotics are agents that are foreign to the biological system but can regulate their metabolism by binding to different xenobiotic receptors (XRs) to produce toxic substances. Modulation of XRs in different preclinical studies have shown benefits in the stroke outcome. Therefore, targeting XRs may be a future therapeutic strategy for stroke intervention. The present review briefly discusses various implications of xenobiotics and their receptors to evolve as a potential therapeutic target for prospective use as an adjunctive therapy for stroke.

Atypical functions of xenobiotic receptors in lipid and glucose metabolism.

Xenobiotic receptors are traditionally defined as xenobiotic chemical-sensing receptors, the activation of which transcriptionally regulates the expression of enzymes and transporters involved in the metabolism and disposition of xenobiotics. Emerging evidence suggests that "xenobiotic receptors" also have diverse endobiotic functions, including their effects on lipid metabolism and energy metabolism. Dyslipidemia is a major risk factor forcardiovascular disease, diabetes, obesity, metabolic syndrome, stroke, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Understanding the molecular mechanism by which transcriptional factors, including the xenobiotic receptors, regulate lipid homeostasis will help to develop preventive and therapeutic approaches. This review describes recent advances in our understanding the atypical roles of three xenobiotic receptors: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), in metabolic disorders, with a particular focus on their effects on lipid and glucose metabolism. Collectively, the literatures suggest the potential values of AhR, PXR and CAR as therapeutic targets for the treatment of NAFLD, NASH, obesity and diabetes, and cardiovascular diseases.

Xenobiotic-sensing nuclear receptors as targets for phthalates-induced lung injury and antagonism of lycopene

Phthalates are extensively used in the production of plastics products and have been verified to induce lung injury. Lycopene (LYC) has proved an effective preventive and can be utilized to prevent phthalates-induced toxicity. However, the role of phthalate in pathogenesis of lung injury remain poorly researched, and little work has been devoted whether LYC could alleviate phthalate-induced lung toxicity via modulating nuclear xenobiotic receptors (NXRs) response. Here, di (2-ethylhexyl) phthalate (DEHP) is used as the representative of phthalates for further studies on toxicity of phthalates and the antagonistic role of LYC in phthalates-induced lung injury. We found that DEHP exposure caused alveoli destruction and alveolar epithelial cells type II damage. Mechanistically, DEHP exposure increased nuclear accumulation of aryl hydrocarbon receptor (AHR) and its downstream genes level, including cytochrome P450-dependent monooxygenase (CYP) 1A1 and CYP1B1. Constitutive androstane receptor (CAR) and their downstream gene level, including CYP2E1 are also increased after phthalates exposure. Significantly, LYC supplementation relieves lung injury from DEHP exposure by inhibiting the activation of NXRs. We confirm that NXRs plays a key role in phthalates-induced lung injury. Our study showed that LYC may have a positive role in alleviating the toxicity effects of phthalates, which provides an effective strategy for revising phthalates-induced injury.

Xenobiotic Receptors, a Journey of Rewards.

The xenobiotic nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) were discovered or characterized in 1998. PXR and CAR have since been defined as master regulators of xenobiotic responses through their transcriptional regulation of drug-metabolizing enzymes and transporters. This article aims to provide an overview on the discovery of PXR and CAR as xenobiotic receptors.

RF03 | PMON287 Examining the role of Constitutive Androstane Receptor during Imidacloprid exposure

Abstract Imidacloprid (IMI) is a neonicotinoid pesticide used for pest control and seed treatments. It mimics nicotine and selectively targets insect nicotinic acetylcholine receptors to induce paralysis and death. Popularly used worldwide, IMI residue is readily detectable in crops, the environment, and human samples. Gastrointestinal symptoms in patients as well as defective gut barrier and hepatoxicity in animal models have been reported subsequent to IMI exposure. However, the mechanism underlying IMI toxicity in mammals is unclear. Pesticide exposure frequently activates xenobiotic nuclear receptors, like constitutive androstane receptor (CAR), to induce detoxification phase I and phase II genes. We found that IMI exposure in wild-type (WT) mice induced hepatic expression of Cyp2b10, a bona fide target of CAR. This data led us to investigate the role of CAR in alleviating IMI toxicity. We dosed wild-type (WT) and Car-/- mice with 50mg/kg BW IMI, twice daily for 21 days and collected serum, liver, and intestine tissues. The absence of CAR resulted in a three-fold increased accumulation of IMI within the liver as well as a 6% increase in body weight. Intriguingly, IMI exposure resulted in hepatic inflammatory pockets in WT mice but did not induce serum liver injury markers (ALT and AST) in either WT or Car-/- mice. We quantified the expression of genes involved in detoxification and oxidative stress within the liver and ileum using qRT-PCR. We found Car-/-mice had significantly blunted expression of Cyp-P450 enzymes in the ileum. To compare gut function, we measured organ coefficient and examined ileal histology using Alcian Blue/PAS staining. We found the absence of CAR altered small intestine (SI) morphology independent of IMI exposure suggesting a basal role of CAR in maintaining overall SI morphology. Car-/-mice also exhibited increased SI weight and length and shorter villi height. AB-PAS staining showed IMI reduced ileal mucin production in WT mice but not Car-/- mice. To further examine CAR's role in the xenobiotic metabolism in the ileum, we will compare microbial diversity and bile acid pools with and without IMI exposure. Our results suggest IMI is not overtly toxic, but the absence of xenobiotic nuclear receptor CAR allows increased accumulation of IMI in the liver and disrupts the structure and Cyp gene expression in the intestine. Presentation: Saturday, June 11, 2022 1:18 p.m. - 1:23 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

DEHP triggers a damage severity grade increase in the jejunum in quail (Coturnix japonica) by disturbing nuclear xenobiotic receptors and the Nrf2-mediated defense response

As a plasticizer, di-2-ethylhexyl phthalate (DEHP) has been listed as a potential endocrine disruptor by The World Health Organization. The toxicity of DEHP has been widely studied, but its toxicity on the digestive tract of birds has not been clarified. Female quail were treated by gavage with DEHP (250, 500, 750 mg/kg), with the blank and vehicle control groups reserved. The result showed that DEHP raised the damage severity grade, and decreased the ratio of villus length to crypt depth. The content and activity of cytochrome P450 system (CYP450s) were increased by DEHP. DEHP interfered with the transcription of nuclear xenobiotic receptors (NXRs), CYP isoforms, and the nuclear factor-E2-related factor 2 (Nrf2) signaling pathway. This study revealed DEHP could cause the imbalance in CYP450s mediated by NXRs, and then promote Nrf2 mediated antioxidant defense. This study provided new evidence about the mechanisms of DEHP-induced toxic effects on digestive tract.

Chicken xenobiotic receptor upregulates the BCRP/ABCG2 transporter

The transporter breast cancer resistance protein (BCRP, encoded by ABCG2) influences the bioavailability and elimination of numerous substrate drugs during clinical therapy. The xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) reportedly regulate functional expression of BCRP in mammalian species. However, it is unknown whether chicken xenobiotic receptor (CXR) regulates the expression and activity of BCRP. This study aimed to investigate the role of CXR in regulation of BCRP in chicken using in vitro and in vivo models. CXR was expressed in the main drug-metabolizing tissues of chickens, and its expression correlated well with that of the prototypical target genes CYP2H1 and ABCG2. BCRP expression was upregulated, and transporter activity was increased, in chicken primary hepatocytes exposed to the CXR agonist metyrapone. Using RNA interference and ectopic expression techniques to manipulate the cellular CXR status, we confirmed that ABCG2 gene regulation depended on CXR. In vivo experiments showed that metyrapone induced BCRP in the liver, kidney, duodenum, and jejunum of chickens. Coadministration of metyrapone significantly changed the pharmacokinetic behavior of orally administered florfenicol (substrate of chicken BCRP), with a lower Cmax (4.62 vs. 7.35 µg/mL, P < 0.01) and AUC0-t (15.83 vs. 24.18 h·mg/L, P < 0.01) as well as a higher Tmax (0.96 vs. 0.79 h, P < 0.05) and Cl/F (0.13 vs. 0.08 L/h/kg, P < 0.05). Together, our data suggest that CXR is involved in regulation of BCRP, and consequently, coadministration of a CXR agonist can affect the pharmacokinetic behavior of an orally administered BCRP substrate.

Aryl Hydrocarbon Receptor Agonism Antagonizes the Hypoxia-driven Inflammation in Cystic Fibrosis.

Hypoxia contributes to the exaggerated yet ineffective airway inflammation that fails to oppose infections in cystic fibrosis (CF). However, the potential for impairment of essential immune functions by HIF-1α (hypoxia-inducible factor 1α) inhibition demands a better comprehension of downstream hypoxia-dependent pathways that are amenable for manipulation. We assessed here whether hypoxia may interfere with the activity of AhR (aryl hydrocarbon receptor), a versatile environmental sensor highly expressed in the lungs, where it plays a homeostatic role. We used murine models of Aspergillus fumigatus infection invivo and human cells invitro to define the functional role of AhR in CF, evaluate the impact of hypoxia on AhR expression and activity, and assess whether AhR agonism may antagonize hypoxia-driven inflammation. We demonstrated that there is an important interferential cross-talk between the AhR and HIF-1α signaling pathways in murine and human CF, in that HIF-1α induction squelched the normal AhR response through an impaired formation of the AhR:ARNT (aryl hydrocarbon receptor nuclear translocator)/HIF-1β heterodimer. However, functional studies and analysis of the AhR genetic variability in patients with CF proved that AhR agonism could prevent hypoxia-driven inflammation, restore immune homeostasis, and improve lung function. This study emphasizes the contribution of environmental factors, such as infections, in CF disease progression and suggests the exploitation of hypoxia:xenobiotic receptor cross-talk for antiinflammatory therapy in CF.

The mechanisms of aluminum-induced immunotoxicity in chicks

Aluminum (Al) is a ubiquitous environmental pollutant representing a significant global health hazard to human and animal health, including chicks. Al toxicity causes oxidative stress, leading to tissue injury, and consequently causes various diseases. NRF2 signaling is vital for protecting cells against oxidative stress. Nuclear xenobiotic receptors are activated by exogenous toxins, thereby inducing the transcription of cytochrome P450 enzyme systems (CYP450s) isoforms involved in xenobiotic metabolism and transport. However, little is known about Al-induced oxidative stress, nuclear xenobiotic receptors and fibrosis in chicks and the mechanisms involved. In this study, male chicks were treated with 0 mg/kg and 500 mg/kg Al2(SO4)3 to evaluate the mechanisms for Al-induced immunotoxicity. Histopathology revealed pathological injury, fibrin aggregation, disruption of the Nuclear Xenobiotic Receptors, and alteration of CYP450s homeostasis in Al-treated chicks due to oxidative stress. Notably, regulation of the NRF2 pathway and CYP450s and fibrosis-related genes was found to play a vital role in inhibiting immunotoxicity. This study provides new insights regarding the mechanisms of Al-induced immunotoxicity, including activation of the nuclear xenobiotic receptors, triggering oxidative stress, and altering the homeostasis of CYP450s in chicks. Further, it provides a theoretical basis for controlling Al exposure and highlights the importance of further studying its mechanisms to provide additional information for formulating preventive measures.

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

Xenobiotic receptors, such as the pregnane X receptor, regulate multiple host physiologic 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 focuses on recent efforts to derive potentially nontoxic microbial metabolite chemical mimics that could one day be developed as drugs combating xenobiotic receptor-modifying pathophysiology. The review will include our perspective on the field and recommend certain directions for future research. SIGNIFICANCE STATEMENT: Xenobiotic receptors (XRs) regulate host drug metabolism, cellular metabolism, and immunity. Their presence in host intestines allows them to function not only as xenosensors but also as a response 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 toward discovery of novel chemical mimics as potential drugs of the future for diseases such as inflammatory bowel disease.

New insights into vitamin K biology with relevance to cancer.

Phylloquinone (vitamin K1) and menaquinones (vitamin K2 family) are essential for post-translational γ-carboxylation of a small number of proteins, including clotting factors. These modified proteins have now been implicated in diverse physiological and pathological processes including cancer. Vitamin K intake has been inversely associated with cancer incidence and mortality in observational studies. Newly discovered functions of vitamin K in cancer cells include activation of the steroid and xenobiotic receptor (SXR) and regulation of oxidative stress, apoptosis, and autophagy. We provide an update of vitamin K biology, non-canonical mechanisms of vitamin K actions, the potential functions of vitamin K-dependent proteins in cancer, and observational trials on vitamin K intake and cancer.