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Document Type

Campus-Only Access for Five (5) Years

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Food Science

Year Degree Awarded

2017

Month Degree Awarded

February

First Advisor

Hang Xiao

Subject Categories

Food Chemistry

Abstract

In this thesis, the tissue distribution and in vivo biotransformation of nobiletin in rodents were demonstrated on three types of rodents, i.e.A-J female mice, CD-1 male mice and male F344 male rats. The effects of colonic metabolites of CD-1 mice on colonic carcinogenesis and inflammation were determined.

In order to mimic the long-term dietary consumption of PMFs from food or dietary supplements, we applied oral administration by mixing PMFs with standard diet to rodents who have free access to food. Moreover, nobiletin (NBT), one of the most abundant PMFs in nature, and its major metabolties were incubated with mice liver S9 to investigate the in vitro biotransformation in liver. The digesta (food under digestion) from small intestine of mice orally adminsitrated with NBT were collected and incubated with microflora from of mice administrated with base diet to investigate the effects of microbiome on biotransformation. NBT and its three metabolites, i.e. 3’-demethylnobiletin (N1), 4’-demethylnobiletin (N2), and 3’, 4’-di-demethylnobiletin (N3) in tissues ranging from brain, kidney, liver, spleen, stomach, small intestine, cecum, colon and blood of three different rodents were determined by HPLC.

The results showed that PMFs was extensively metabolized to N1, N2 and N3 as well as their glucuronide/sulfate conjugates. N2 was the most abundant metabolite for all types of rodents. In the contrast to the metabolites in small intestine, where conjugated metabolites dominant, most metabolites colon were in free form. The microflora was proved to be able to deconjugate the metabolites, producing free form metabolites which possess higher bioactivities than parent compound and their conjugates counterparts.

Considering the high level of the bioactive metabolites localized in colonic mucosa, we further investigated the anti-cancer and anti-inflammation effect of metabolites localized in colon. The results suggested that the anti-cancer and anti-inflammation effect of orally administrated nobiletin was induced by the colonic metabolites. These metabolites complex can induce cell cycle arrest and apoptosis in cancer cells.

As a summary, these studies provided a thorough information of PMFs in vivo biotransformation, the tissue distribution of biological activity related metabolites as well as the implication of the metabolism on colorectal cancer and inflammation.

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