title: Evaluation of cytochrome P450-derived eicosanoids in humans with stable atherosclerotic cardiovascular disease.
abstract: OBJECTIVE
  Preclinical and genetic epidemiologic studies suggest that modulating cytochrome P450 (CYP)-mediated arachidonic acid metabolism may have therapeutic utility in the management of coronary artery disease (CAD). However, predictors of inter-individual variation in CYP-derived eicosanoid metabolites in CAD patients have not been evaluated to date. Therefore, the primary objective was to identify clinical factors that influence CYP epoxygenase, soluble epoxide hydrolase (sEH), and CYP ω-hydroxylase metabolism in patients with established CAD.
  
  
  METHODS
  Plasma levels of epoxyeicosatrienoic acids (EETs), dihydroxyeicosatrienoic acids (DHETs), and 20-hydroxyeicosatetraenoic acid (20-HETE) were quantified by HPLC-MS/MS in a population of patients with stable, angiographically confirmed CAD (N=82) and healthy volunteers from the local community (N=36). Predictors of CYP epoxygenase, sEH, and CYP ω-hydroxylase metabolic function were evaluated by regression.
  
  
  RESULTS
  Obesity was significantly associated with low plasma EET levels and 14,15-EET:14,15-DHET ratios. Age, diabetes, and cigarette smoking also were significantly associated with CYP epoxygenase and sEH metabolic activity, while only renin-angiotensin system inhibitor use was associated with CYP ω-hydroxylase metabolic activity. Compared to healthy volunteers, both obese and non-obese CAD patients had significantly higher plasma EETs (P<0.01) and epoxide:diol ratios (P<0.01), whereas no difference in 20-HETE levels was observed (P=NS).
  
  
  CONCLUSIONS
  Collectively, these findings suggest that CYP-mediated eicosanoid metabolism is dysregulated in certain subsets of CAD patients, and demonstrate that biomarkers of CYP epoxygenase and sEH, but not CYP ω-hydroxylase, metabolism are altered in stable CAD patients relative to healthy individuals. Future studies are necessary to determine the therapeutic utility of modulating these pathways in patients with CAD.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Theken
authors.forename: Robert N
authors.initials: RN
authors.lastname: Schuck
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.forename: Bryant
authors.initials: B
authors.lastname: Tran
authors.forename: Kyle
authors.initials: K
authors.lastname: Ellis
authors.forename: Almasa
authors.initials: A
authors.lastname: Bass
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
authors.forename: Michael C
authors.initials: MC
authors.lastname: Wu
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hinderliter
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: George A
authors.initials: GA
authors.lastname: Stouffer
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000097:blood; D000367:Age Factors; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000453:epidemiology; D003430:Cross-Sectional Studies; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000097:blood / Q000201:enzymology / Q000453:epidemiology; D015777:Eicosanoids / Q000097:blood*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D009657:North Carolina; D009765:Obesity / Q000097:blood / Q000201:enzymology / Q000453:epidemiology; D012044:Regression Analysis; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects; D053719:Tandem Mass Spectrometry
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D015415:Biomarkers; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D042926:Cytochrome P-450 CYP4A; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid