Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers.

Mohebati A, Milne GL, Zhou XK, Duffield-Lillico AJ, Boyle JO, Knutson A, Bosworth BP, Kingsley PJ, Marnett LJ, Brown PH, Akpa EG, Szabo E, Dannenberg AJ
Cancer Prev Res (Phila). 2013 6 (7): 646-55

PMID: 23682075 · PMCID: PMC3707304 · DOI:10.1158/1940-6207.CAPR-13-0083

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.

©2013 AACR.

MeSH Terms (20)

Adult Arachidonate 5-Lipoxygenase Biomarkers Celecoxib Chromatography, Liquid Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Female Humans Hydroxyurea Leukotriene E4 Lipoxygenase Inhibitors Male Maximum Tolerated Dose Prognosis Prostaglandins Pyrazoles Smoking Sulfonamides Tandem Mass Spectrometry

Connections (3)

This publication is referenced by other Labnodes entities:

Links