Itraconazole cis -diastereoisomers activate aryl hydrocarbon receptor AhR and pregnane X receptor PXR and induce CYP1A1 in human cell lines and human hepatocytes

Štěpánková, Martina; Pastorková, Barbora; Bachleda, Petr; Dvořák, Zdeněk

doi:10.1016/j.tox.2017.04.002

Cited by 7 publications

(2 citation statements)

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“…Despite data presented here indicating the role of the microbiota-Trp metabolites-AhR axis, other signaling pathways might be also implicated in the beneficial effects of Trp on intestinal epithelial integrity. For example, farnesoid x receptor (FXR) or pregnane x receptor (PXR) can participate in the regulation of mucosal homeostasis in mice and in the function of cultured hepatocytes ( Pavek, 2016 ; Stepankova et al, 2017 ). Although we could detect only five major metabolites of Trp in the contents of the piglet large intestine, potential roles of other quantitatively minor products of Trp in gut function cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Dietary L-Tryptophan Modulates the Structural and Functional Composition of the Intestinal Microbiome in Weaned Piglets

et al. 2018

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Background: Intestinal microbiota plays an important role in regulating metabolism, physiology, and immune response of the host. L-Tryptophan (Trp) are metabolized by several genera of bacteria. It remains largely unknown whether Trp can regulate the composition and diversity of the intestinal microbiota and contribute to intestinal homeostasis.Methods: A total of 126 weaning piglets were fed a corn- and soybean meal-based diet supplemented with 0, 0.2, or 0.4% Trp for 4 weeks. The intestinal microbiota was measured by using bacterial 16S rRNA gene-based high-throughput sequencing methods. Metabolites of Trp and short-chain fatty acids (SCFAs) in the hindgut were determined by high-performance liquid chromatography and gas chromatography, respectively. The mRNA levels for aromatic hydrocarbon receptor (AhR), tumor necrotic factor-α (TNF-α), interleukin-8 (IL-8), and protein abundances of tight junction proteins were determined.Results: Compared with the control group, Trp supplementation enhanced piglet growth performance and markedly altered the intestinal microbial composition as evidenced by enhanced alpha and beta diversity in the microbiome (P < 0.05). The abundances of Prevotella, Roseburia, and Succinivibrio genera were enriched, but those of Clostridium sensu stricto and Clostridium XI, opportunistic pathogens, were decreased with dietary Trp supplementation. Analysis of metabolic pathways indicated enhanced indole alkaloid biosynthesis and Trp metabolism, which was validated by elevated concentrations of 3-indoleacetic acid and indole in the intestinal contents of Trp-supplemented piglets (P < 0.05). These changes in Trp metabolites were correlated with activation of AhR and cytochrome p4501 A1 (CYP1A1) in cecum and colonic tissues, and with a decrease in the intestinal mucosal IL-8 mRNA level. Moreover, the protein abundances for zonula occluden (ZO)-1 and occludin were upregulated by Trp supplementation in colonic tissues.Conclusion: Dietary Trp supplementation altered intestinal microbial composition and diversity, improved intestinal mucosal barrier function, activated AhR signaling, and downregulated expression of inflammatory cytokines in the large intestine of weaned piglets. These results indicate a crosstalk between dietary Trp and intestine in nutrition, microbial metabolism, and mucosal immunity.

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Section: Discussionmentioning

confidence: 99%

Dietary L-Tryptophan Modulates the Structural and Functional Composition of the Intestinal Microbiome in Weaned Piglets

et al. 2018

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“…The focus of the literature review was on azole compounds that are or have been in use for agricultural purposes and/or the treatment of other plants. No consideration was given to pharmaceutical azole fungicides, for which, however, also various interactions with xenosensing nuclear receptors and their target genes have been observed, for example in the case of fluconazole [9][10][11], oxiconazole [12], itraconazole [11,13], and voriconazole [14]. Similarly, ketoconazole and its analogs mediate liver toxicity in a PXR-dependent manner [15].…”

Section: Literature Review Of Azole Effects On Xenosensing Receptorsmentioning

confidence: 99%

The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity

Marx‐Stoelting

Knebel

Braeuning

2020

Cells

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Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.

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Induction of Cytochrome P450 Systems

2020

Human Drug Metabolism

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Itraconazole cis -diastereoisomers activate aryl hydrocarbon receptor AhR and pregnane X receptor PXR and induce CYP1A1 in human cell lines and human hepatocytes

Cited by 7 publications

References 37 publications

Dietary L-Tryptophan Modulates the Structural and Functional Composition of the Intestinal Microbiome in Weaned Piglets

Dietary L-Tryptophan Modulates the Structural and Functional Composition of the Intestinal Microbiome in Weaned Piglets

The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity

Induction of Cytochrome P450 Systems

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