The Metabolism Of Polymethoxyflavone And Its Implication In Colon Cancer Inhibition

We have previously reported inhibitory effects of 5‐hydroxy nobiletin (5HN, a unique citrus flavonoid) on colon cancer. Herein, we investigated colon metabolism of 5HN in rodents and its implication in colon cancer inhibition. Using LC‐MS and NMR, we identified 3 major metabolites of 5HN in GI tract of mice and rats, i.e. 3′,4′,5‐trihydroxy nobiletin (M1), 3′,5‐dihydroxy nobiletin (M2), and 4′,5‐dihydroxy nobiletin (M3). In small intestine mucosa, about 55% of 5HN and 95% of its metabolites were in conjugated forms (glucuronide and sulfate). In contrast, only 10% of 5HN and 25% of metabolites were in conjugated forms in colonic mucosa. This is presumably due to de‐conjugation by colonic microflora. 5HN and its metabolites in conjugated forms lacked inhibitory effects on colon cancer cells in comparison with their free forms. In the mice fed with 0.05% 5HN in diet for 1 week, the levels of free 5HN and its metabolites ranged from 1~10 μg/g tissue in colonic mucosa (equivalent to 3–26 μM, assuming 1 gram of tissue occupies 1 mL of volume). All three metabolites were more potent in inhibiting colon cancer cell growth than 5HN, especially, M2, e.g., IC 50 s of M2 were 50~100‐fold lower than those of 5HN. Our results provide a strong basis for using 5HN to inhibit colon cancer due to its desirable colonic metabolism profile.