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Levels of Prostaglandin E Metabolite and Leukotriene E₄ Are Increased in the Urine of Smokers: Evidence that Celecoxib Shunts Arachidonic Acid into the 5-Lipoxygenase Pathway

Authors' Affiliations: Departments of ¹ Epidemiology and Biostatistics and ² Surgery, Memorial Sloan-Kettering Cancer Center; Departments of ³ Public Health and ⁴ Medicine, Weill Cornell Medical College, New York, New York; ⁵ Pharmaceutical Development Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁶ Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee

Requests for reprints: Andrew J. Dannenberg, Department of Medicine and Weill Cornell Cancer Center, 525 East 68th Street, Room F-206, New York, NY 10065. Phone: 212-746-4403; Fax: 212-746-4885; E-mail: ajdannen{at}med.cornell.edu.

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 E₄ (LTE₄), 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 LTE₄ were determined. Baseline levels of PGE-M and LTE₄ were positively associated with smoking status; levels of PGE-M and LTE₄ 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 LTE₄, an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE₄ 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 LTE₄ 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.

Key Words: Smoking • Biomarker • Celecoxib • 5-lipoxygenase • cardiovascular toxicity

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