Dataset Information

Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor.

ABSTRACT: Emerging evidence indicates that the aryl hydrocarbon receptor (AhR) plays a crucial role in normal physiologic homeostasis. Additionally, aberrant AhR signaling leads to several pathologic states in the lung and liver. Activation of AhR transcriptionally induces phase I (CYP1A) detoxifying enzymes. Although the effects of the classic AhR ligands such as 3-methylcholanthrene and dioxins on phase 1 enzymes are well studied in rodent lung, liver, and other organs, the toxicity profiles limit their use as therapeutic agents in humans. Hence, there is a need to identify and investigate nontoxic AhR ligands not only to understand the AhR biology but also to develop the AhR as a clinically relevant therapeutic target. Leflunomide is a Food and Drug Administration-approved drug in humans that is known to have AhR agonist activity in vitro. Whether it activates AhR and induces phase 1 enzymes in vivo is unknown. Therefore, we tested the hypothesis that leflunomide will induce pulmonary and hepatic CYP1A enzymes in C57BL/6J wild-type mice, but not in AhR-null mice. We performed real-time reverse-transcription polymerase chain reaction analyses for CYP1A1/2 mRNA expression, western blot assays for CYP1A1/2 protein expression, and ethoxyresorufinO-deethylase assay for CYP1A1 catalytic activity. Leflunomide increased CYP1A1/A2 mRNA, protein, and enzymatic activities in wild-type mice. In contrast, leflunomide failed to increase pulmonary and hepatic CYP1A enzymes in AhR-null mice. In conclusion, we provide evidence that leflunomide induces pulmonary and hepatic CYP1A enzymes via the AhR.

SUBMITTER: Patel A

PROVIDER: S-EPMC4658494 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor.

Patel Ananddeep A Zhang Shaojie S Paramahamsa Maturu M Jiang Weiwu W Wang Lihua L Moorthy Bhagavatula B Shivanna Binoy B

Drug metabolism and disposition: the biological fate of chemicals 20150928 12

Emerging evidence indicates that the aryl hydrocarbon receptor (AhR) plays a crucial role in normal physiologic homeostasis. Additionally, aberrant AhR signaling leads to several pathologic states in the lung and liver. Activation of AhR transcriptionally induces phase I (CYP1A) detoxifying enzymes. Although the effects of the classic AhR ligands such as 3-methylcholanthrene and dioxins on phase 1 enzymes are well studied in rodent lung, liver, and other organs, the toxicity profiles limit their ...[more]

PMID: 26417045

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Project description:BackgroundPollutant particles containing environmentally persistent free radicals (EPFRs) are formed during many combustion processes (e.g. thermal remediation of hazardous wastes, diesel/gasoline combustion, wood smoke, cigarette smoke, etc.). Our previous studies demonstrated that acute exposure to EPFRs results in dendritic cell maturation and Th17-biased pulmonary immune responses. Further, in a mouse model of asthma, these responses were enhanced suggesting exposure to EPFRs as a risk factor for the development and/or exacerbation of asthma. The aryl hydrocarbon receptor (AHR) has been shown to play a role in the differentiation of Th17 cells. In the current study, we determined whether exposure to EPFRs results in Th17 polarization in an AHR dependent manner.ResultsExposure to EPFRs resulted in Th17 and IL17A dependent pulmonary immune responses including airway neutrophilia. EPFR exposure caused a significant increase in pulmonary Th17 cytokines such as IL6, IL17A, IL22, IL1β, KC, MCP-1, IL31 and IL33. To understand the role of AHR activation in EPFR-induced Th17 inflammation, A549 epithelial cells and mouse bone marrow-derived dendritic cells (BMDCs) were exposed to EPFRs and expression of Cyp1a1 and Cyp1b1, markers for AHR activation, was measured. A significant increase in Cyp1a1 and Cyp1b1 gene expression was observed in pulmonary epithelial cells and BMDCs in an oxidative stress and AHR dependent manner. Further, in vivo exposure of mice to EPFRs resulted in oxidative stress and increased Cyp1a1 and Cyp1b1 pulmonary gene expression. To further confirm the role of AHR activation in pulmonary Th17 immune responses, mice were exposed to EPFRs in the presence or absence of AHR antagonist. EPFR exposure resulted in a significant increase in pulmonary Th17 cells and neutrophilic inflammation, whereas a significant decrease in the percentage of Th17 cells and neutrophilic inflammation was observed in mice treated with AHR antagonist.ConclusionExposure to EPFRs results in AHR activation and induction of Cyp1a1 and in vitro this is dependent on oxidative stress. Further, our in vivo studies demonstrated a role for AHR in EPFR-induced pulmonary Th17 responses including neutrophilic inflammation.

Dataset Information

Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor.

Publications

Leflunomide Induces Pulmonary and Hepatic CYP1A Enzymes via Aryl Hydrocarbon Receptor.

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