Bioavailability of Flavonoids: A Review of Their Membrane Transport and the Function of Bilitranslocase in Animal and Plant Organisms

Abstract

Fruits and vegetables are rich in flavonoids, and ample epidemiological data show that diets rich in fruits and vegetables confer protection against cardiovascular, neurodegenerative and inflammatory diseases, and cancer. However, flavonoid bioavailability is reportedly very low in mammals and the molecular mechanisms of their action are still poorly known. This review focuses on membrane transport of flavonoids, a critical determinant of their bioavailability. Cellular influx and efflux transporters are reviewed for their involvement in the absorption of flavonoids from the gastro-intestinal tract and their subsequent tissue distribution. A focus on the mammalian bilirubin transporter bilitranslocase (TCDB 2.A.65.1.1) provides further insight into flavonoid bioavailability and its relationship with plasma bilirubin (an endogenous antioxidant). The general function of bilitranslocase as a flavonoid membrane transporter is further demonstrated by the occurrence of a plant homologue in organs (petals, berries) where flavonoid biosynthesis is most active. Bilitranslocase appears associated with sub-cellular membrane compartments and operates as a flavonoid membrane transporter.

The silkworm Green b locus encodes a quercetin 5- O -glucosyltransferase that produces green cocoons with UV-shielding properties

“…S4. In mammals, flavonoid glucuronides are excreted out of enterocytes to both the serosal and luminal sides of intestinal epithelium via efflux transporters (19,23,24). Thus, we speculate that glucosylation at the 5-O position might allow or facilitate the efficient uptake and transport of quercetin from the midgut to the silk glands by altering interactions with efflux and/or influx transporters.…”

“…However, it is more likely that 5-O-glucosylation of quercetin dramatically increases the bioavailability of quercetin in the silkworm by changing its solubility, permeability, metabolism, excretion, target tissue uptake, or disposition. In mammals, after absorption from the small intestine, flavonoids undergo extensive metabolism, generating different conjugation forms such as glucuronides and sulfates (19,20). The bioavailability of flavonoids is generally low and can be problematic in pharmacological studies (19,21,22), as these conjugation reactions can enhance the elimination of lipophilic xenobiotics (19,21).…”

“…In mammals, after absorption from the small intestine, flavonoids undergo extensive metabolism, generating different conjugation forms such as glucuronides and sulfates (19,20). The bioavailability of flavonoids is generally low and can be problematic in pharmacological studies (19,21,22), as these conjugation reactions can enhance the elimination of lipophilic xenobiotics (19,21). It has been shown that glucuronidation of flavonoids can influence the bioavailability of flavonoids in mammals partly by changing their permeability and interactions with their putative transporters such as ATP-binding cassette superfamily transporters (19-21, 23, 24).…”

“…It has been shown that glucuronidation of flavonoids can influence the bioavailability of flavonoids in mammals partly by changing their permeability and interactions with their putative transporters such as ATP-binding cassette superfamily transporters (19-21, 23, 24). However, exact mechanisms for absorption, transport, and disposition of flavonoids are not well understood in any animal system (19,21), and the degree to which the site specificity in the glucuronidation step is important for the bioavailability of flavonoids remains unclear (19,21,24). It is notable that the glucosylation reaction at the 5-O position of quercetin caused a marked increase in the amount of flavonoids in silk glands, hemolymph, and cocoon (Table S1).…”

Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA)

“…In general, the bioavailability of flavonoid glycosides has been extensively studied since they are ubiquitous micronutrients in various diets [39,40]. It has been reported that deglycosylation of such compounds by β-glucosidase in the small intestine and by the colonic microflora is often required before absorption can occur [41,42]. The flavonoids aglycones, either occurring as such in plants or resulting from hydrolysis, displayed various permeability behaviours.…”