title: 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.
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: Ananddeep
authors.initials: A
authors.lastname: Patel
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: Maturu
authors.initials: M
authors.lastname: Paramahamsa
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: Weiwu
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.
authors.forename: Bhagavatula
authors.initials: B
authors.lastname: Moorthy
authors.affiliation: Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas shivanna@bcm.edu.
authors.forename: Binoy
authors.initials: B
authors.lastname: Shivanna
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis*; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis*; D065693:Cytochrome P-450 Enzyme Inducers / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007555:Isoxazoles / Q000378:metabolism* / Q000494:pharmacology; D000077339:Leflunomide; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065693:Cytochrome P-450 Enzyme Inducers; D007555:Isoxazoles; D000077339:Leflunomide; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse