Levels of prostaglandin E metabolite, the major urinary metabolite of prostaglandin E2, are increased in smokers

Abstract

Purpose: Increased levels of cyclooxygenase-2 and prostaglandin E2 (PGE2) have been observed in tobacco-related malignancies of the upper aerodigestive tract. Moreover, exposure to tobacco smoke can stimulate the synthesis of PGE2. Recent evidence suggests that urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE2 production. In this study, we investigated whether levels of urinary PGE-M were increased in smokers and in patients with head and neck squamous cell carcinoma (HNSCC).

Experimental design: Fifty-eight HNSCC cases and 29 age- and gender-matched healthy controls were prospectively enrolled in the study. A detailed smoking history and single void urine specimen were obtained from each participant. Levels of urinary PGE-M were quantified in a blinded fashion using mass spectrometry and compared with smoking history and tumor status.

Results: Adjusted for case-control matching, median urinary PGE-M levels were significantly higher in ever smokers (15.7 ng/mg creatinine) compared with never smokers (9.9 ng/mg creatinine) for the entire study population (n = 87, P = 0.005). Concentrations of urinary PGE-M were nearly doubled in ever smokers (15.2 ng/mg creatinine) versus never smokers (7.8 ng/mg creatinine) among healthy controls (P = 0.001). Higher PGE-M levels were observed in current versus former smokers and in those with greater pack-year exposure. A significant difference in amounts of PGE-M was not observed in patients with HNSCC versus healthy controls.

Conclusions: Increased levels of urinary PGE-M were observed in smokers. Urinary PGE-M may have use as a noninvasive biomarker of the effects of tobacco smoke exposure.

Fig. 1

Biosynthesis of PGE-M. Arachidonic acid, released from membrane phospholipids by phospholipase A₂ (PLA₂) is metabolized by COX-1and COX-2 to PGH₂. PGH₂ is converted to PGE₂ by microsomal PGE synthase-1 (mPGES-1). PGE₂ is metabolized to PGE-M in a series of steps including a reaction catalyzed by 15-PGDH.

Fig. 2

Levels of urinary PGE-Min HNSCC cases versus healthy controls. A, urinary PGE-M levels [median (range)] are not significantly elevated in 58 HNSCC cases [15.4 (2.4–69.7) ng/mg creatinine] compared with 29 healthy controls [12.6 (1.5–68.5) ng/mg creatinine, P = 0.07]. B, ROC curve was estimated by the nonparametric empirical estimate. Urinary PGE-M was unable to discriminate between HNSCC patients and controls. C, urinary PGE-M levels are not altered by surgical resection of HNSCC in 13 patients.

Fig. 3

Levels of urinary PGE-M are increased in ever smokers. A, urinary PGE-M levels [median (range)] are elevated in 53 ever smokers [15.7 (2.4–69.7) ng/mg creatinine] compared with 34 never smokers [9.9 (1.5–27.5) ng/mg creatinine] among HNSCC cases and controls combined (P = 0.005). B, levels of urinary PGE-M were increased in ever (n = 13) versus never (n = 16) smokers among healthy tumor-free controls (15.2 versus 7.8 ng/mg creatinine, P = 0.001).

Fig. 4

Urinary PGE-M levels as a function of smoking history. A statistically significant increase in urinary PGE-M levels [median (range)] was observed from never [9.9 (1.5–27.5) ng/mg creatinine] to former [14.7 (2.4–68.5) ng/mg creatinine] to current [22.6 (6.8–69.7) ng/mg creatinine] smoking status among HNSCC cases and controls combined (P = 0.004).