Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology.
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ABSTRACT:
SUBMITTER: Nebert DW
PROVIDER: S-EPMC2606007 | biostudies-literature | 2008 Dec
REPOSITORIES: biostudies-literature
Publications
Endogenous functions of the aryl hydrocarbon receptor (AHR): intersection of cytochrome P450 1 (CYP1)-metabolized eicosanoids and AHR biology.
Nebert Daniel W DW Karp Christopher L CL
The Journal of biological chemistry 20080818 52
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Project description:The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4(+) T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4(+) T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.
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Project description:The effects of endothelium-derived hyperpolarizing factors have been attributed to cytochrome P450-derived epoxyeicosatrienoic acids (EETs), but the regulation and role of EETs in endothelial dysfunction remain largely unexplored. Hypertension is a primary risk factor for renal dysfunction, which is frequently accompanied by various systemic diseases induced by endothelial dysfunction in the microcirculation. We previously reported that the endothelial growth factor midkine (MK) enhances hypertension in a model of CKD. Here, we investigated the hypothesis that MK regulates EET activity and thereby BP. MK gene-deleted mice were resistant to hypertension and developed less glomerulosclerosis and proteinuria after administration of a nitric oxide synthase (NOS) inhibitor in the setting of uninephrectomy. The hypertension observed in uninephrectomized wild-type mice after NOS inhibition was ameliorated by anti-MK antibody. MK-deficient mice produced higher amounts of EETs, and EETs dominantly regulated BP in these mice. Furthermore, MK administration to MK-deficient mice recapitulated the BP control observed in wild-type mice. EETs also dominantly regulated renal blood flow, which may influence renal function, in MK-deficient mice. Taken together, these results suggest that the MK/EET pathway is physiologically engaged in BP control and could be a target for the treatment of hypertension complicated by endothelial dysfunction.
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Project description:Cytochrome P450 eicosanoids play important roles in brain function and disease through their complementary actions on cell-cell communications within the neurovascular unit (NVU) and mechanisms of brain injury. Epoxy- and hydroxyeicosanoids, respectively formed by cytochrome P450 epoxygenases and ω-hydroxylases, play opposing roles in cerebrovascular function and in pathological processes underlying neural injury, including ischemia, neuroinflammation and oxidative injury. P450 eicosanoids also contribute to cerebrovascular disease risk factors, including hypertension and diabetes. We summarize studies investigating the roles P450 eicosanoids in cerebrovascular physiology and disease to highlight the existing balance between these important lipid signaling molecules, as well as their roles in maintaining neurovascular homeostasis and in acute and chronic neurovascular and neurodegenerative disorders.
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Project description:The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 epoxygenases that have vasodilatory properties similar to that of endothelium-derived hyperpolarizing factor. The cytochrome P450 isoform CYP2J2 was cloned and identified as a potential source of EETs in human endothelial cells. Physiological concentrations of EETs or overexpression of CYP2J2 decreased cytokine-induced endothelial cell adhesion molecule expression, and EETs prevented leukocyte adhesion to the vascular wall by a mechanism involving inhibition of transcription factor NF-kappaB and IkappaB kinase. The inhibitory effects of EETs were independent of their membrane-hyperpolarizing effects, suggesting that these molecules play an important nonvasodilatory role in vascular inflammation.
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Project description:The lung epithelial barrier serves as a guardian towards environmental insults and responds to allergen encounter with a cascade of immune reactions that can possibly lead to inflammation. Whether the environmental sensor aryl hydrocarbon receptor (AhR) together with its downstream targets cytochrome P450 (CYP1) family members contribute to the regulation of allergic airway inflammation remains unexplored. By employing knockout mice for AhR and for single CYP1 family members, we found that AhR-/- and CYP1B1-/- but not CYP1A1-/- or CYP1A2-/- animals display enhanced allergic airway inflammation compared to WT. Expression analysis, immunofluorescence staining of murine and human lung sections and bone marrow chimeras suggest an important role of CYP1B1 in non-hematopoietic lung epithelial cells to prevent exacerbation of allergic airway inflammation. Transcriptional analysis of murine and human lung epithelial cells indicates a functional link of AhR to barrier protection/inflammatory mediator signaling upon allergen challenge. In contrast, CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and to an increased availability of the AhR ligand kynurenic acid following allergen challenge. Thus, differential CYP1 family member expression and signaling via the AhR in epithelial cells represents an immunoregulatory layer protecting the lung from exacerbation of allergic airway inflammation.
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Project description:Eicosanoids are a class of functionally bioactive lipid mediators derived from the metabolism of long-chain polyunsaturated fatty acids (PUFAs) mediated by multiple enzymes of three main branches, including cyclooxygenases (COXs), lipoxygenases (LOXs), and cytochrome P450s (CYPs). Recently, the role of eicosanoids derived by COXs and LOXs pathways in the control of physiological and pathological processes associated with cancer has been well documented. However, the role of CYPs-mediated eicosanoids, such as epoxyeicosatrienoic acids (EETs), epoxyoctadecenoic acids (EpOMEs), epoxyeicosatetraenoic acids (EpETEs), and epoxydocosapentaenoic acids (EDPs), as well as hydroxyeicosatetraenoic acids (HETEs), in tumorigenesis and cancer progression have not been fully elucidated yet. Here we summarized the association of polymorphisms of CYP monooxygenases with cancers and the pleiotropic functions of CYP monooxygenase-mediated eicosanoids (EETs, EpOMEs, EpETE, EDPs, and 20-HETE) in the tumorigenesis and metastasis of multiple cancers, including but not limited to colon, liver, kidney, breast and prostate cancers, which hopefully provides valuable insights into cancer therapeutics. We believe that manipulation of CYPs with or without supplement of ω-3 PUFAs to regulate eicosanoid profile is a promising strategy to prevent and/or treat cancers.
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Project description:The 1-deoxysphingolipids (1-deoxySLs) are atypical sphingolipids (SLs) that are formed when serine palmitoyltransferase condenses palmitoyl-CoA with alanine instead of serine during SL synthesis. The 1-deoxySLs are toxic to neurons and pancreatic β-cells. Pathologically elevated 1-deoxySLs cause the inherited neuropathy, hereditary sensory autonomic neuropathy type 1 (HSAN1), and are also found in T2D. Diabetic sensory polyneuropathy (DSN) and HSAN1 are clinically very similar, suggesting that 1-deoxySLs may be implicated in both pathologies. The 1-deoxySLs are considered to be dead-end metabolites, as they lack the C1-hydroxyl group, which is essential for the canonical degradation of SLs. Here, we report a previously unknown metabolic pathway, which is capable of degrading 1-deoxySLs. Using a variety of metabolic labeling approaches and high-resolution high-accuracy MS, we identified eight 1-deoxySL downstream metabolites, which appear to be formed by cytochrome P450 (CYP)4F enzymes. Comprehensive inhibition and induction of CYP4F enzymes blocked and stimulated, respectively, the formation of the downstream metabolites. Consequently, CYP4F enzymes might be novel therapeutic targets for the treatment of HSAN1 and DSN, as well as for the prevention of T2D.
| S-EPMC5234722 | biostudies-literature
Project description:Transcriptional analysis of human lung epithelial cells indicates a functional link of AhR to barrier protection/inflammatory mediator signaling upon allergen challenge.
2022-05-23 | GSE196949 | GEO
Project description:Primary brain tumors, both malignant and benign, are diagnosed in adults at an incidence rate of approximately 23 people per 100 thousand. The role of AhR in carcinogenesis has been a subject of debate, given that this protein may act as either an oncogenic protein or a tumor suppressor in different cell types and contexts. Lately, there is growing evidence that aryl hydrocarbon receptor (AhR) plays an important part in the development of brain tumors. The role of AhR in brain tumors is complicated, depending on the type of tumor, on ligands that activate AhR, and other features of the pathological process. In this review, we summarize current knowledge about AhR in relation to brain tumors and provide an overview of AhR's potential as a therapeutic target.
| S-EPMC7215596 | biostudies-literature
Project description:OBJECTIVE:Accumulating preclinical and epidemiologic evidence has emerged to suggest that modulation of cytochrome P450 (CYP)-mediated eicosanoid metabolism may be a viable vascular protective therapeutic strategy for the secondary prevention of coronary artery disease (CAD). The functional relationship between CYP-derived eicosanoid metabolite levels and vascular dysfunction in humans with established CAD, however, has not been evaluated. Therefore, we characterized the relationship between inter-individual variation in soluble epoxide hydrolase (sEH) and CYP ?-hydroxylase metabolism and established vascular function phenotypes predictive of prognosis in a cohort of patients with atherosclerotic cardiovascular disease. METHODS:Plasma epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHET), and 20-hydroxyeicosatetraenoic acid (20-HETE) levels were quantified by HPLC-MS/MS in 106 patients with stable, angiographically-confirmed CAD. Relationships between biomarkers of CYP-mediated eicosanoid metabolism and vascular function phenotypes were evaluated by Pearson's correlation. RESULTS:A significant inverse association was observed between 20-HETE levels (a biomarker of CYP ?-hydroxylase metabolism) and brachial artery flow-mediated dilation (r = -0.255, p = 0.010). An inverse association was also observed between 14,15-EET:DHET ratios (a biomarker of sEH metabolism) and both monocyte chemoattractant protein-1 levels (r = -0.252, p = 0.009) and a consolidated cellular adhesion molecule 'score' reflecting the levels of E-selectin and P-selectin (r = -0.216, p = 0.027). No associations with C-reactive protein or epithelial neutrophil-activating protein-78 levels were observed. CONCLUSIONS:Collectively, these findings demonstrate that enhanced CYP ?-hydroxylase and sEH metabolic function are associated with more advanced endothelial dysfunction and vascular inflammation, respectively, in patients with established atherosclerotic cardiovascular disease. These findings lay the foundation for future clinical research in this area.
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