Flavonoids are important dietary phytochemicals with broad human exposures and a variety of claimed biological effects. Although traditional sources of flavonoids are fruits and vegetables, dietary supplements have become an important source of flavonoids. The enthusiasm for all things about flavonoids expressed by scientists and public alike has sometimes overlooked an important point: these compounds are usually not bioavailable or have very low bioavailability. The current review focused on factors that affect bioavailability of flavonoids, which in turn impact their efficacy and toxicity. These factors include physicochemical and biological ones, with the emphasis on the latter, including membrane permeation, enzymatic metabolism, and excretion by efflux transporters. Current evidence indicates that naturally occurring flavonoid glycosides typically need to be de-glycosylated before they are absorbed, because intact flavonoid glycosides are poorly absorbed. However, once absorbed, flavonoid aglycones undergo rapid and extensive first-pass metabolism via conjugation and subsequent excretion of the conjugates, which makes them poorly bioavailable. Fortunately, the presence of enteric and enterohepatic recycling allows the flavonoids to be accumulated in vivo over time, because the recycling increases contact time between the flavonoids and target tissues. We believe that continued studies in this area will help scientists devise a better means to improve oral bioavailability of flavonoids so we can one day fully enjoy the health benefits of ingesting flavonoids.
Scope
Enterohepatic recycling is often thought to involve mostly phase II metabolites generated in the liver. This study aims to determine if direct biliary excretion of extrahepatically generated glucuronides would also enable recycling.
Methods and Results
Conventional and modified intestinal perfusion models along with intestinal and liver microsomes were used to determine the contribution of extrahepatically derived glucuronides. Glucuronidation of four flavonoids (genistein, biochanin A, apigenin and chrysin @2.5–20 μM) were generally more rapid in the hepatic than intestinal microsomes. Furthermore, when aglycones (@10 μM each) were perfused, larger (1.7–9 fold) amounts of glucuronides were found in the bile than in the luminal perfusate. However, higher concentrations of glucuronides were not found in jugular vein than portal vein, and apigenin glucuronide actually displayed a significantly lower concentration in jugular vein (<1 nM) than portal vein (≈4 nM). A direct portal infusion of 4 flavonoid glucuronides (5.9–10.4 μM perfused @2 ml/hr) showed that the vast majority (>65%) of the glucuronides (except for biochanin A glucuronide) administered were efficiently excreted into the bile.
Conclusion
Direct biliary excretion of extrahepatically generated flavonoid glucuronides is a highly efficient clearance mechanism, which should enable enterohepatic recycling of flavonoids without hepatic conjugating enzymes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.