title: Bioactive lipid profiling reveals drug target engagement of a soluble epoxide hydrolase inhibitor in a murine model of tobacco smoke exposure.
abstract: The inflammatory process underlying chronic obstructive pulmonary disease (COPD) may be caused by tobacco smoke (TS) exposure. Previous studies show that epoxyeicosatrienoic acids (EETs) possess promising anti-inflammatory properties, therefore stabilization of EETs and other fatty acid epoxides through inhibition of soluble epoxide hydrolase (sEH) was investigated in mouse models of acute and sub-chronic inflammation caused by TS exposure. During the entire TS exposure, the potent sEH inhibitor 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS) was given via drinking water. To assess drug target engagement of TUPS, a tandem mass spectrometry method was used for bioactive lipid profiling of a broad range of fatty acid metabolites, including EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as epoxides and diols derived from other fatty acids. Several, but not all, plasma epoxide/diol ratios increased in mice treated with sEH inhibitor, compared to non-treated mice suggesting a wider role for sEH involving more fatty acid precursors besides arachidonic acid. This study supports qualitative use of epoxide/diol ratios explored by bioactive lipid profiling to indicate drug target engagement in mouse models of TS exposure relevant to COPD, which may have ramifications for future therapeutic interventions of sEH.
authors.affiliation: Department of Chemistry, Umeå University, 901 87 Umeå, Sweden; Department of Entomology and Comprehensive Cancer Center, University of California - Davis, One Shields Ave, Davis, CA 95616, USA.
authors.forename: Malin L
authors.initials: ML
authors.lastname: Nording
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California - Davis, One Shields Ave, Davis, CA 95616, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Center for Health and the Environment, University of California - Davis, Old Davis Rd, Davis, CA 95616, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Hoang
authors.affiliation: Center for Health and the Environment, University of California - Davis, Old Davis Rd, Davis, CA 95616, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zamora
authors.affiliation: Center for Health and the Environment, University of California - Davis, Old Davis Rd, Davis, CA 95616, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Uyeminami
authors.affiliation: Center for Health and the Environment, University of California - Davis, Old Davis Rd, Davis, CA 95616, USA.
authors.forename: Imelda
authors.initials: I
authors.lastname: Espiritu
authors.affiliation: Center for Health and the Environment, University of California - Davis, Old Davis Rd, Davis, CA 95616, USA.
authors.forename: Kent E
authors.initials: KE
authors.lastname: Pinkerton
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California - Davis, One Shields Ave, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California - Davis, One Shields Ave, Davis, CA 95616, USA; Medical Service, Veterans Affairs Palo Alto Healthcare System, PAVIR and Division of Immunology/Rheumatology, Stanford University School of Medicine, Palo Alto, CA.
authors.forename: Ayala
authors.initials: A
authors.lastname: Luria