β-Glucuronidase activity and mitochondrial dysfunction: the sites where flavonoid glucuronides act as anti-inflammatory agents

Abstract

Epidemiological and experimental studies suggest that the consumption of flavonoid-rich diets decreases the risk of various chronic diseases such as cardiovascular diseases. Although studies on the bioavailability of flavonoids have been well-characterized, the tissue and cellular localizations underlying their biological mechanisms are largely unknown. The development and application of novel monoclonal antibodies revealed that macrophages could be the major target of dietary flavonoids in vivo. Using macrophage-like cell lines in vitro, we examined the molecular basis of the interaction between the macrophages and flavonoids, especially the glucuronide metabolites. We have found that extracellular β-glucuronidase secreted from macrophages is essential for the bioactivation of the glucuronide conjugates into the aglycone, and that the enzymatic activity, which requires an acidic pH, is promoted by the increased secretion of lactate in response to the mitochondrial dysfunction. This review describes our recent findings indicating the molecular mechanisms responsible for the anti-inflammatory activity of dietary flavonoids within the inflammation sites. We propose that the extracellular activity of β-glucuronidase associated with the status of the mitochondrial function in the target cells might be important biomarkers for the specific sites where the glucuronides of dietary flavonoids can act as anti-atherosclerotic and anti-inflammatory agents in vivo.

Phase II Conjugates of Urolithins Isolated from Human Urine and Potential Role ofβ-Glucuronidases in Their Disposition

“…The b-glucuronidase released by macrophages was shown to be essential for activation of quercetin glucuronide conjugates. Its enzymatic activity, which requires acidic pH, was promoted by increased secretion of lactate in response to mitochondrial dysfunction (Kawai, 2014).…”

5,7‐Dihydroxyflavone Analogues May Regulate Lipopolysaccharide‐Induced Inflammatory Responses by Suppressing IκBα‐Linked Akt and ERK5 Phosphorylation in RAW 264.7 Macrophages

“…However, their anti-inflammatory effects are mild [35]. In addition, the relationships between their chemical structures and biological activities are not fully understood.…”

At the interface of antioxidant signalling and cellular function: Key polyphenol effects

“…The same situation could apply for other (poly)phenols . Extracellular β‐glucuronidase secreted from macrophages and in the vascular bed can also lead to de‐conjugation of the glucuronide conjugates of (poly)phenols and deliver the aglycone at a higher local concentration, which due to its higher lipid solubility accumulates in tissues . In support of this notion, a recent acute human study reported effects of quercetin in hypertensive subjects related to increased plasma glutathione levels, an antioxidant biomarker; these effects were proportional to the bioavailability of quercetin and the rate of deconjugation of the glucuronide in tissues .…”

“…It has also been postulated that inflammation enhances intracellular β‐glucuronidase leading cells exposed to glucuronide conjugates of quercetin to release the more bioactive aglycone. The same situation could apply for other (poly)phenols . Extracellular β‐glucuronidase secreted from macrophages and in the vascular bed can also lead to de‐conjugation of the glucuronide conjugates of (poly)phenols and deliver the aglycone at a higher local concentration, which due to its higher lipid solubility accumulates in tissues .…”