Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways

Abstract

Flavonoids, existing mainly as glycosides in nature, have multiple “claimed” beneficial effects in humans. Flavonoids are extensively metabolized in enterocytes and hepatocytes by phase II enzymes such as UGTs and SULTs to form glucuronides and sulfates, respectively. These glucuronides and sulfates are subsequently excreted via ABC transporters (e.g., MRP2 or BCRP). Therefore, it is the interplay between phase II enzymes and efflux transporters that affects the disposition of flavonoids and leads to the low bioavailability of flavonoid aglycones. Flavonoids can also serve as chemical regulators that affect the activity or expression levels of phase II enzymes including UGTs, SULTs and GSTs, and transporters including P-gp, MRP2, BCRP, OATP and OAT. In general, flavonoids may exert the inhibitory or inductive effects on the phase II enzymes and transporters via multiple mechanisms that may involve different nuclear receptors. Since flavonoids may affect the metabolic pathways shared by many important clinical drugs, drug-flavonoid interaction is becoming an increasingly important concern. This review article focused on the disposition of flavonoids and effects of flavonoids on relevant enzymes (e.g. UGTs and SULTs) and transporters (e.g. MRP2 and BCRP) involved in the interplay between phase II enzymes and efflux transporters. The effects of flavonoids on other metabolic enzymes (e.g. GSTs) or transporters (e.g. P-gp, OATP and OAT) are also addressed but that is not the emphasis of this review.

The interaction of dietary flavonoids with xanthine oxidase in vitro: molecular property-binding affinity relationship aspects

“…where K a is the binding constant and n is the number of binding sites per enzyme molecule. According to formulas (2) and 3, the values of "F 0 /F" and "(F 0 À F)/F" could be observed in each "[Q]" of samples. Then, the linear regression equation between the "F 0 /F" values and "[Q]" values was obtained, and the slope means "K sv ".…”

“…Dietary avonoids exist widely in many plant foods, such as fruits, vegetables, nuts, and tea. 1,2 Over 10 000 avonoids have been separated and identied from plants, including anthocyanidins, avones, avonols, avanones, and isoavones. 3 Investigation of avonoids from dietary sources has attracted considerable interest because of their nutritional and medical effects in humans.…”

Pennyroyal and gastrointestinal cells: multi-target protection of phenolic compounds against t-BHP-induced toxicity

“…[44][45][46] The viability assays did not demonstrate cellular toxic effects for the experimented infusion concentrations (Fig. 48 At the incubation conditions no chemical hydrolyses occurs: the compounds present are O-heterosides, requiring very acid pH conditions and high temperature in order to break the link between the sugar moieties and the aglycones. However, nuclear morphology alterations may be earlier visible than other toxicological end-points.…”

Quercetin, Morin, Luteolin, and Phloretin Are Dietary Flavonoid Inhibitors of Monocarboxylate Transporter 6

“…14,15 Flavonoids have been demonstrated to be substrates and potent inhibitors of many members of the organic anion transporter family, including MCTs, 16,17 and cause significant drug–food interactions. 18–21 More specifically, flavonoids have been reported to interact with organic anion transporters MCT1, 16 OAT1, 22 and OATP1B1.…”