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Nutrition and Cancer

Human Fecal Water Inhibits COX-2 in Colonic HT-29 Cells: Role of Phenolic Compounds¹

Pernilla C. Karlsson², Ulrika Huss^2,*, Andrew Jenner, Barry Halliwell, Lars Bohlin^* and Joseph J. Rafter³

Department of Medical Nutrition, Karolinska Institutet, Novum, S-141 86 Huddinge, Sweden; ^* Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, S-751 23 Uppsala, Sweden; and Department of Biochemistry, National University of Singapore, Singapore 117597

³To whom correspondence should be addressed. E-mail: joseph.rafter{at}mednut.ki.se.

The inducible enzyme cyclooxygenase-2 (COX-2) plays a major role in the regulation of inflammation and possibly in the development of colon cancer. The aim of the present study was to screen for COX-2 inhibitors in samples of fecal water (the aqueous phase of feces) and investigate whether phenolic compounds are responsible for any observed effects on COX-2. Volunteers (n = 20) were recruited and asked to supply a 24-h stool sample. Fecal water samples were prepared and analyzed by GC-MS for their content of phenolic compounds. These samples were also evaluated for their effects on COX-2 protein levels (Western blot) and prostaglandin (PG)E₂ production in tumor necrosis-–stimulated HT-29 cells and pure enzymatic activity in a COX-2–catalyzed prostaglandin biosynthesis in vitro assay. The major phenolic compounds identified were phenylpropionic acid, phenylacetic acid, cinnamic acid, and benzoic acid derivatives. Of 13 fecal water samples analyzed, 12 significantly decreased PGE₂ production (range 5.4–39.7% inhibition, P-value < 0.05) compared with control cells and 13 of 14 samples analyzed decreased COX-2 protein levels in HT-29 cells (19–63% inhibition). Of the 20 fecal water samples, 2 also weakly inhibited enzymatic activity of purified COX-2 (22–24% inhibition). Three compounds identified in fecal water, 3-phenylpropionic acid, 3-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)-propionic acid, decreased the protein level at 250 µmol/L (15–62% inhibition). This study shows for the first time that human fecal water contains components that can affect both the COX-2 protein level and enzymatic activity.

KEY WORDS: • COX-2 inhibitors • colon cancer • fecal water • phenolic compounds • HT-29 cells