Tissue distribution of nobiletin and its metabolites in mice after oral administration of nobiletin

Nobiletin (NBT), a major citrus polymethoxyflavone, has been shown to have various beneficial bioactivities such as anti‐inflammatory and anti‐carcinogenic effects. However, the in vivo absorption, metabolism, and tissue distribution of NBT is poorly understood. In this study, A/J mice were fed NBT (250, 500, or, 1000 ppm in diet) for 16 weeks, and then the tissue levels of NBT and its major metabolites i.e. 3′‐hydroxylnobiletin (N1), 4′‐hydroxylnobiletin (N2) and 3′,4′‐dihydroxylnobiletin (N3) were determined by HPLC analysis. Our results showed that NBT was extensively metabolized in the small intestine to glucuronide and sulfate conjugates of N1, N2 and N3. In contrast, these conjugates were largely deconjugated in the colon presumably by colonic microflora. It was also evident that considerable amount of N1 and N2 were transformed to N3 in the colon. Moreover, different tissues showed distinct patterns of metabolite accumulation. For example, N2 was dominant in the small intestine and liver, while N3 was dominant in the spleen and colon. Very interestingly, NBT showed high accumulation in the brain, which was even much higher than that in the liver. The plasma levels of total NBT and its metabolites were as high as 25μM. Overall, we revealed detailed information on absorption, metabolism, and tissue distribution of NBT in mice, which is very important for further understanding of bioactivities of NBT. Grant Funding Source : AICR, NIH, NAS and USDA