Celecoxib use and circulating oxylipins in a colon polyp prevention trial

Abstract

Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E2 are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (P<0.05) and differences were greater among non-aspirin users. LOX derived 5- and 8-HETE were elevated with celecoxib and positively associated with systolic blood pressure (P = 0.011 and P = 0.019 respectively). 20-HETE, a prohypertensive androgen-sensitive CYP450 metabolite was higher with celecoxib absent aspirin and was positively associated with SBP in men (P = 0.040) but not women. Independent of celecoxib or aspirin, LOX derived metabolites from ARA were strongly associated with SBP including 5- and 8-HETE. These findings support oxylipins, particularly the ARA LOX-derived, in blood pressure control and indicate that pharmacologic inhibition of COX-2 has effects on LOX and CYP450 ARA metabolism that contribute to hypertension in some patients.

Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers

“…In a placebo-controlled phase III selenium/celecoxib trial to prevent colorectal adenomatous polyps, blood oxylipins from celecoxib treated participants showed higher levels of individual CYP450 and LOX metabolites and lower levels of COX-derived metabolites compared to placebo treated participants 26 . However, since circulating oxylipin profiles are unlikely to represent tissue profiles, and as we have previously shown that ibuprofen was associated with proteasome and metabolic dysfunction in livers 27 , the oxylipin profiles of livers from ibuprofen treated mice were investigated.…”

MS-based targeted metabolomics of eicosanoids and other oxylipins: Analytical and inter-individual variabilities

“…Of note, even for these widely used and well characterized drugs, responses are complex and impacts on oxylipin patterns are often broader than expected(51). For instance, the use of celecoxib, a specific COX-2 inhibitor, in patients M A N U S C R I P TA C C E P T E D ACCEPTED MANUSCRIPT22 with colon polyp, was associated with increased levels of CYP-and LOX-derived oxylipins(126), which could be a result of substrate shunting into these alternative pathways. Other drugs not specifically designed to modulate enzymes of the oxylipin pathways can also influence oxylipin patterns.…”

Oxylipins as Biomarkers for Aromatase Inhibitor-Induced Arthralgia (AIA) in Breast Cancer Patients

“…There were four PUFAs (EPA, DHA, ARA, and LA) plus 62 of their oxygenated lipid metabolites (oxylipins) in the original analytical platform. Of the 62 oxylipins, 43 had >80% of samples with levels above the limit of detection [ 14 ]. Table S1 shows the mean ± SD at baseline, three, and six months for the four PUFAs that were quantified, and Table S2 shows the mean ± SD at baseline, three, and six months for the 43 oxylipins.…”

“…The presence of underlying inflammation and the nociceptive activity of oxylipins, may be a contributing factor for pain [ 11 , 12 , 13 ]. Our group previously published an overview of the oxylipin pathway and biological outcomes [ 14 ]. Oxylipin profiles are implicated in the development of inflammatory conditions including rheumatoid arthritis [ 15 ].…”