Involvement of CYP1B1 in interferon γ‐induced alterations of epithelial barrier integrity

Alhouayek, Mireille; Gouveia-Figueira, Sandra; Hammarström, Marie‐Louise; Fowler, Christopher J.

doi:10.1111/bph.14122

Cited by 7 publications

(4 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, it reveals that upregulated CYP1A1 and CYP1B1 expression is preserved during inflammatory crosstalk between Wnt5A and proinflammatory IL-1β in human coronary artery endothelial cells. This novel finding from human vascular endothelial cells isolated from coronary artery, a primary cell system retaining original tissue characteristics (Franscini et al, 2004;Skaria et al, 2019), is in accordance with previous findings that proinflammatory cytokines, in contrast to their suppressive effects on drug metabolizing pathways in hepatocytes (Morgan, 2009;Wu and Lin, 2019), stimulate the transcription of CYP enzymes in extrahepatic cell systems (Smerdová et al, 2014;Alhouayek et al, 2018). Previous studies showed that CYP1A1, involved in transformation of xenobiotics to toxic metabolites, also metabolizes a broad spectrum of drugs and consequently account for drugs' adverse effects.…”

Section: Discussionsupporting

confidence: 91%

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

2021

View full text Add to dashboard Cite

Downregulation of drug metabolizing enzymes and transporters by proinflammatory mediators in hepatocytes, enterocytes and renal tubular epithelium is an established mechanism affecting pharmacokinetics. Emerging evidences indicate that vascular endothelial cell expression of drug metabolizing enzymes and transporters may regulate pharmacokinetic pathways in heart to modulate local drug bioavailability and toxicity. However, whether inflammation regulates pharmacokinetic pathways in human cardiac vascular endothelial cells remains largely unknown. The lipid modified protein Wnt5A is emerging as a critical mediator of proinflammatory responses and disease severity in sepsis, hypertension and COVID-19. In the present study, we employed transcriptome profiling and gene ontology analyses to investigate the regulation of expression of drug metabolizing enzymes and transporters by Wnt5A in human coronary artery endothelial cells. Our study shows for the first time that Wnt5A induces the gene expression of CYP1A1 and CYP1B1 enzymes involved in phase I metabolism of a broad spectrum of drugs including chloroquine (the controversial drug for COVID-19) that is known to cause toxicity in myocardium. Further, the upregulation of CYP1A1 and CYP1B1 expression is preserved even during inflammatory crosstalk between Wnt5A and the prototypic proinflammatory IL-1β in human coronary artery endothelial cells. These findings stimulate further studies to test the critical roles of vascular endothelial cell CYP1A1 and CYP1B1, and the potential of vascular-targeted therapy with CYP1A1/CYP1B1 inhibitors in modulating myocardial pharmacokinetics in Wnt5A-associated inflammatory and cardiovascular diseases.

show abstract

Section: Discussionsupporting

confidence: 91%

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

2021

View full text Add to dashboard Cite

show abstract

“…The cytochrome P450 (CYP) family 1 enzymes are mainly controlled by aryl hydrocarbon receptor (AhR), which is involved in phase I xenobiotic metabolism in the intestine 32 . Induction of CYP1A1 and CYP1B1 enhances inflammatory responses and alters the intestinal epithelial barrier function 33 , 34 . Consistent with previous findings that azo dyes can induce CYP1 enzymes 35 , AhR was activated (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Chronic exposure to synthetic food colorant Allura Red AC promotes susceptibility to experimental colitis via intestinal serotonin in mice

et al. 2022

View full text Add to dashboard Cite

Chemicals in food are widely used leading to significant human exposure. Allura Red AC (AR) is a highly common synthetic colorant; however, little is known about its impact on colitis. Here, we show chronic exposure of AR at a dose found in commonly consumed dietary products exacerbates experimental models of colitis in mice. While intermittent exposure is more akin to a typical human exposure, intermittent exposure to AR in mice for 12 weeks, does not influence susceptibility to colitis. However, exposure to AR during early life primes mice to heightened susceptibility to colitis. In addition, chronic exposure to AR induces mild colitis, which is associated with elevated colonic serotonin (5-hydroxytryptamine; 5-HT) levels and impairment of the epithelial barrier function via myosin light chain kinase (MLCK). Importantly, chronic exposure to AR does not influence colitis susceptibility in mice lacking tryptophan hydroxylase 1 (TPH1), the rate limiting enzyme for 5-HT biosynthesis. Cecal transfer of the perturbed gut microbiota by AR exposure worsens colitis severity in the recipient germ-free (GF) mice. Furthermore, chronic AR exposure elevates colonic 5-HT levels in naïve GF mice. Though it remains unknown whether AR has similar effects in humans, our study reveals that chronic long-term exposure to a common synthetic colorant promotes experimental colitis via colonic 5-HT in gut microbiota-dependent and -independent pathway in mice.

show abstract

“…After binding with the ligand, AhR translocates to the nucleus and binds with AhR nuclear translocator, forming a heterodimer, which modulates the target gene (CYP1A2) expression through binding with xenobiotic-responsive elements [54,55]. It is also found that downregulation of CYP1A2 is observed during inflammation [56], whereas AhR activation protects intestinal epithelium from enterocolitis by promoting CYP1A2 expression [57][58][59], and that indole derivatives activate AhR to promote IL-22 secretion, which boosts intestinal mucosal defense [60]. Interestingly, the present study found a significantly elevated expression of AhR, CYP1A2, and IL-22 in the jejunum of the FMT group, indicating that gut microbiota (probably Lactobacillus)-produced metabolites protect jejunum from inflammation and promote intestinal homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Fecal microbiota transplantation improves chicken growth performance by balancing jejunal Th17/Treg cells

Akhtar

Pan

et al. 2023

Microbiome

View full text Add to dashboard Cite

Background Intestinal inflammation has become a threatening concern in chicken production worldwide and is closely associated with Th17/Treg cell imbalance. Several studies described that gut microbiota is significantly implicated in chicken growth by modulating intestinal immune homeostasis and immune cell differentiation. Whether reshaping gut microbiota by fecal microbiota transplantation (FMT) could improve chicken growth by balancing Th17/Treg cells is an interesting question. Results Here, the chickens with significantly different body weight from three different breeds (Turpan cockfighting × White Leghorn chickens, white feather chickens, and yellow feather chickens) were used to compare Th17 and Treg cells. qPCR and IHC staining results indicated that Th17 cell-associated transcriptional factors Stat3 and rorγt and cytokines IL-6, IL-17A, and IL-21 were significantly (P < 0.05) higher in the jejunum of low body weight chickens, while Treg cell-associated transcriptional factor foxp3 and cytokines TGF-β and IL-10 were significantly (P < 0.05) lower in the jejunum of low body weight chickens, indicating imbalanced Th17/Treg cells were closely related to chicken growth performance. Transferring fecal microbiota from the healthy donor with better growth performance and abundant Lactobacillus in feces to 1-day-old chicks markedly increased growth performance (P < 0.001), significantly decreased Th17 cell-associated transcriptional factors and cytokines, and increased Treg cell-associated transcriptional factors and cytokines in the jejunum (P < 0.05). Furthermore, FMT increased the abundance of Lactobacillus (FMT vs Con; 84.98% vs 66.94%). Besides, the metabolites of tryptophan including serotonin, indole, and 5-methoxyindoleacetate were increased as well, which activated their receptor aryl-hydrocarbon-receptor (AhR) and expressed more CYP1A2 and IL-22 to maintain Th17/Treg cell balance and immune homeostasis. Conclusion These findings suggested that imbalanced Th17/Treg cells decreased chicken growth performance, while FMT-reshaped gut microbiota, i.e., higher Lactobacilli, increased chicken growth performance by balancing Th17/Treg cells.

show abstract

Involvement of CYP1B1 in interferon γ‐induced alterations of epithelial barrier integrity

Cited by 7 publications

References 67 publications

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

Transcriptional Regulation of Drug Metabolizing CYP Enzymes by Proinflammatory Wnt5A Signaling in Human Coronary Artery Endothelial Cells

Chronic exposure to synthetic food colorant Allura Red AC promotes susceptibility to experimental colitis via intestinal serotonin in mice

Fecal microbiota transplantation improves chicken growth performance by balancing jejunal Th17/Treg cells

Contact Info

Product

Resources

About