title: Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers.
abstract: COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 ± 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.
authors.affiliation: Department of Surgery (Head and Neck Service), Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Arash
authors.initials: A
authors.lastname: Mohebati
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Duffield-Lillico
authors.forename: Jay O
authors.initials: JO
authors.lastname: Boyle
authors.forename: Allison
authors.initials: A
authors.lastname: Knutson
authors.forename: Brian P
authors.initials: BP
authors.lastname: Bosworth
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.forename: Esther G
authors.initials: EG
authors.lastname: Akpa
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000328:Adult; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D015415:Biomarkers / Q000652:urine; D000068579:Celecoxib; D002853:Chromatography, Liquid; D051546:Cyclooxygenase 2 / Q000737:chemistry / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D017999:Leukotriene E4 / Q000652:urine*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D020714:Maximum Tolerated Dose; D011379:Prognosis; D011453:Prostaglandins / Q000652:urine*; D011720:Pyrazoles / Q000494:pharmacology*; D012907:Smoking; D013449:Sulfonamides / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; C060526:7-hydroxy-5,11-dioxotetranorprostane-1,16-dioic acid; D017999:Leukotriene E4; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000068579:Celecoxib; C063449:zileuton; D006918:Hydroxyurea