Glucuronides of phytoestrogen flavonoid enhance macrophage function via conversion to aglycones by β‐glucuronidase in macrophages

Abstract

IntroductionFlavonoids are converted to inactive metabolites like glucuronides in the gut, and circulate mainly as glucuronides in blood stream, resulting in low concentrations of active aglycones in plasma. It is therefore unclear how oral flavonoids exert their effects in tissues. We recently reported the plasma pharmacokinetics of some flavonoids and suggested the possibility that the absorbed flavonoids modified macrophage functions leading to enhance bacterial clearance. We aimed to confirm their pharmacological profiles focusing on tissue macrophages.MethodsPseudoinfection was induced by intradermal injection of FITC‐conjugated and killed Staphylococcus aureus into the ears of mice treated with or without genistein 7‐O‐glucuronide (GEN7G, 1 mg/kg, i.v.). FACS analysis was performed on single cell suspensions dispersed enzymatically from the skin lesions at 6 h post pseudoinfection to evaluate phagocytic activities of monocytes/macrophages (CD11b+Ly6G−) and neutrophils (CD11b+Ly6G+). Phagocytosis of the FITC‐conjugated bacteria by four glucuronides including GEN7G was evaluated in cultures of mouse macrophages.ResultsAfter GEN7G injection, genistein was identified in the inflamed ears as well as GEN7G, and the phagocytic activity of CD11b+Ly6G− cells was increased. GEN7G was converted to genistein by incubation with macrophage‐related β‐glucuronidase. Macrophage culture assays revealed that GEN7G increased phagocytosis, and the action was dampened by a β‐glucuronidase inhibitor. Binding of aglycones to estrogen receptors (ERs), putative receptors of flavonoid aglycones, correlated to biological activities, and glucuronidation reduced the binding to ERs. An ER antagonist suppressed the increase of macrophage function by GEN7G, whereas estradiol enhanced phagocytosis as well.ConclusionsThis study suggests a molecular mechanism by which oral flavonoids are carried as glucuronides and activated to aglycones by β‐glucuronidase in tissue macrophages, and contributes to the pharmacological study of glucuronides.

Flavonoid metabolism: the interaction of metabolites and gut microbiota

“…Macrophages showed deglucuronidation activity against quercetin glucuronides and produced more active aglycon than its conjugated metabolites [52][53][54]. Such deglucuronidation systems may control the physiological activity of dietary flavonoids [55,56]. To estimate the physiological activity of flavonoid metabolites, the use of authentic pure molecules is critical.…”

Differential annotation of converted metabolites (DAC-Met): Exploration of Maoto (Ma-huang-tang)-derived metabolites in plasma using high-resolution mass spectrometry

“…Conversely, the concentrations of IG and ILG glucuronide conjugates are much higher than those of the parent compounds (Matsumoto et al 2015). It has been reported that flavonoid-glucuronide is activated as an aglycon by β-glucuronidase in tissue macrophages (Kaneko et al 2017). Likewise, the metabolites in subnetwork A in Fig.…”

“…THMs contain a large number of natural compounds with diverse activities; they act on various sites in the body and the cumulative results of complex interactions are manifested as pharmacological effects on the body. Important metabolic process includes various conjugation reactions affecting the delivery of the active components to target sites (Kaneko et al 2017), and hydrolysis by the microbiome is essential for exerting their pharmacological effects (Ikarashi and Mizoguchi 2016;Oh and Kim 2016;Yamamoto et al 2000). To understand the complex nature of THM metabolism, time-resolved comprehensive compound profiling is essential, where the profiling covers not only the native components of THMs but also their metabolites converted by microbiome and metabolic enzymes in the liver and gastrointestinal tissue.…”

Terfezia boudieri: A Desert Truffle With Anticancer and Immunomodulatory Activities

“…The high activity of aqueous/methanol extract may be explained by the presence of flavonoids in these extracts, as mentioned previously in our phytochemical tests. A previous study on flavonoids indicates that they can enhance macrophage function (45).…”