title: Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway.
abstract: Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E(4) (LTE(4)), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers, and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE(4) were determined. Baseline levels of PGE-M and LTE(4) were positively associated with smoking status; levels of PGE-M and LTE(4) were higher in current versus never smokers. Treatment with 200 mg celecoxib twice daily for 6 +/- 1 days led to a reduction in urinary PGE-M levels in all groups but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE(4), an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE(4) were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the proinflammatory 5-LO pathway. Because 5-LO activity and LTE(4) have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Duffield-Lillico
authors.forename: Jay O
authors.initials: JO
authors.lastname: Boyle
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.forename: Aradhana
authors.initials: A
authors.lastname: Ghosh
authors.forename: Geera S
authors.initials: GS
authors.lastname: Butala
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: Robert A
authors.initials: RA
authors.lastname: Newman
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg