title: Contributions of the three CYP1 monooxygenases to pro-inflammatory and inflammation-resolution lipid mediator pathways.
abstract: All three cytochrome P450 1 (CYP1) monooxygenases are believed to participate in lipid mediator biosynthesis and/or their local inactivation; however, distinct metabolic steps are unknown. We used multiple-reaction monitoring and liquid chromatography-UV coupled with tandem mass spectrometry-based lipid-mediator metabololipidomics to identify and quantify three lipid-mediator metabolomes in basal peritoneal and zymosan-stimulated inflammatory exudates, comparing Cyp1a1/1a2/1b1(⁻/⁻) C57BL/6J-background triple-knockout mice with C57BL/6J wild-type mice. Significant differences between untreated triple-knockout and wild-type mice were not found for peritoneal cell number or type or for basal CYP1 activities involving 11 identified metabolic steps. Following zymosan-initiated inflammation, 18 lipid mediators were identified, including members of the eicosanoids and specialized proresolving mediators (i.e., resolvins and protectins). Compared with wild-type mice, Cyp1 triple-knockout mice exhibited increased neutrophil recruitment in zymosan-treated peritoneal exudates. Zymosan stimulation was associated with eight statistically significantly altered metabolic steps: increased arachidonic acid-derived leukotriene B₄ (LTB₄) and decreased 5S-hydroxyeicosatetraenoic acid; decreased docosahexaenoic acid-derived neuroprotectin D1/protectin D1, 17S-hydroxydocosahexaenoic acid, and 14S-hydroxydocosahexaenoic acid; and decreased eicosapentaenoic acid-derived 18R-hydroxyeicosapentaenoic acid (HEPE), 15S-HEPE, and 12S-HEPE. In neutrophils analyzed ex vivo, elevated LTB₄ levels were shown to parallel increased neutrophil numbers, and 20-hydroxy-LTB₄ formation was found to be deficient in Cyp1 triple-knockout mice. Together, these results demonstrate novel contributions of CYP1 enzymes to the local metabolite profile of lipid mediators that regulate neutrophilic inflammation.
authors: Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
authors: Senad
authors: S
authors: Divanovic
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors: Jesmond
authors: J
authors: Dalli
authors: Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
authors: Lucia F
authors: LF
authors: Jorge-Nebert
authors: Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
authors: Leah M
authors: LM
authors: Flick
authors: Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
authors: Marina
authors: M
authors: Gálvez-Peralta
authors: Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
authors: Nicholas D
authors: ND
authors: Boespflug
authors: Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
authors: Traci E
authors: TE
authors: Stankiewicz
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors: Jonathan M
authors: JM
authors: Fitzgerald
authors: Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
authors: Maheshika
authors: M
authors: Somarathna
authors: Division of Cellular and Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati OH 45229.
authors: Christopher L
authors: CL
authors: Karp
authors: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors: Charles N
authors: CN
authors: Serhan
authors: Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati OH 45267-0056.
authors: Daniel W
authors: DW
authors: Nebert
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008055:Lipids / Q000276:immunology; D055442:Metabolome; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D018836:Inflammation Mediators; D008055:Lipids; D003577:Cytochrome P-450 Enzyme System
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