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: Anna J Duffield-Lillico, Jay O Boyle, Xi Kathy Zhou, Aradhana Ghosh, Geera S Butala, Kotha Subbaramaiah, Robert A Newman, Jason D Morrow, Ginger L Milne, Andrew J Dannenberg
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 2 Issue 4 Pg. 322-9 (Apr 2009) ISSN: 1940-6215 [Electronic] United States
• PMID: 19336727 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Prostaglandins E
• Pyrazoles
• Sulfonamides
• Arachidonic Acid
• Leukotriene E4
• Arachidonate 5-Lipoxygenase
• Cyclooxygenase 2
• Celecoxib

Topics

• Arachidonate 5-Lipoxygenase (drug effects, metabolism)
• Arachidonic Acid (metabolism)
• Celecoxib
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Female
• Humans
• Leukotriene E4 (urine)
• Male
• Middle Aged
• Pneumonia (chemically induced, urine)
• Prostaglandins E (metabolism)
• Pyrazoles (pharmacology)
• Signal Transduction
• Smoking (adverse effects, urine)
• Sulfonamides (pharmacology)