A Protective Role for Arachidonic Acid Metabolites against Advanced Colorectal Adenoma in a Phase III Trial of Selenium

Abstract

Oxylipins derived from arachidonic acid (ARA) have been implicated in the development of colorectal adenomas and colorectal cancer. The primary purpose of this work was to determine the relationship between plasma levels of oxylipins and colorectal adenoma characteristics at study entry, as well as with the development of a new adenoma during follow-up within a Phase III adenoma prevention clinical trial with selenium (Sel). Secondarily, we sought to determine whether the selenium intervention influenced plasma oxylipin levels. Four oxylipins were quantified in stored plasma samples from a subset of Sel study subjects (n = 256) at baseline and at 12-months. There were significantly lower odds of an advanced adenoma at baseline with higher prostaglandin E₂ (PGE₂), with an OR (95% CI) of 0.55 (0.33-0.92), and with 5-hydroxyeicosatetraenoic acid (5-HETE) ((0.53 (0.33-0.94)); and of a large adenoma with higher PGE₂ ((0.52 (0.31-0.87)). In contrast, no associations were observed between any oxylipin and the development of a new adenoma during follow-up. Selenium supplementation was associated with a significantly smaller increase in 5-HETE after 12 months compared to the placebo, though no other results were statistically significant. The ARA-derived oxylipins may have a role in the progression of non-advanced adenoma to advanced, but not with the development of a new adenoma.

Keywords: ARA; arachidonic acid; colon cancer; colorectal adenoma; colorectal neoplasia; oxylipins; selenium.

Figure 1

Arachidonic Acid metabolism via COX-2, CYP450, 5-LOX and 12-LOX. ARA metabolism via COX-2, CYP450, 5-LOX and 12-LOX produces PGE₂, 20-HETE, 5-HETE, and 12-HETE respectively. Only those oxylipins quantified on our platform are illustrated here. Abbreviations: COX-2: cyclooxygenase-2; CYP450: cytochrome P450; 5-LOX: 5-lipoxygenase; 12-LOX: 12-lipoxygenase; PGE₂: prostaglandin E₂; 5-HETE: 5-hydroxyeicosatetraenoic acid; 12-HETE: 12-hydroxyeicosatetraenoic acid.