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The Comparison of Rat and Human Intestinal and Hepatic Glucuronidation of Enterolactone Derived from Flaxseed Lignans

dc.contributor.advisorAlcorn, Janeen_US
dc.contributor.advisorKrol, Eden_US
dc.contributor.committeeMemberOlkowski, Andrewen_US
dc.contributor.committeeMemberRemillard, Freden_US
dc.contributor.committeeMemberWeber, Lynnen_US
dc.creatorLin, Chaojieen_US 2012en_US
dc.description.abstractThe mammalian lignan, enterolactone (EL), is a gut microbe metabolite of plant lignan secoisolariciresinol diglucoside (SDG), which is most abundant in flaxseed. Numerous epidemiological, experimental and clinical studies suggest the protective effects of EL against various chronic diseases such as cancer, cardiovascular disease, and inflammation. However, EL’s oral bioavailability is low and highly variable due to extensive first-pass metabolism, especially glucuronidation, which results in the large amount of glucuronide metabolites but low levels of free EL in human plasma. Hepatocytes and enterocytes express UDP-glucuronosyltransferases (UGT), the enzymes responsible for the conjugation of glucuronic acid to EL. To better understand the contribution of liver and intestine to the first-pass glucuronidation, I conducted an in vitro enzyme kinetic analysis of EL glucuronidation using hepatic and intestinal microsomal fractions from both human and rat. An intrinsic clearance (CLint) value was calculated using the substrate depletion approach. In addition to monitoring substrate depletion, high-pressure liquid chromatography (HPLC) analysis allowed detection of EL glucuronides, which were further substantiated by LC-MS. EL monoglucuronide was identified in rat and human intestinal and liver microsomes. Enzyme kinetic studies indicated the extent of hepatic microsomal glucuronidation exceeded intestinal glucuronidation in both human and rat, while the human liver CLint value was slightly higher than that of rat liver. The CLint value generated in human intestinal microsomes was only one third of the value of human liver, whereas, the CLint of rat jejunum or colon was one-twentieth of rat liver, suggesting the human intestine makes a greater contribution to EL glucuronidation than rat intestine. These results suggest that both liver and intestine contribute to EL glucuronidation and the human intestine may exert a greater influence on the first-pass glucuronidation of EL than rat intestine, thereby significantly decreasing EL’s oral bioavailability. The rat might underestimate the extent of intestinal metabolism of EL relative to human.en_US
dc.subjectenterolactone, flaxseed, glucuronidation, intestine, liver, lignanen_US
dc.titleThe Comparison of Rat and Human Intestinal and Hepatic Glucuronidation of Enterolactone Derived from Flaxseed Lignansen_US
dc.type.materialtexten_US and Nutritionen_US of Saskatchewanen_US of Science (M.Sc.)en_US


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