Transit and Metabolic Pathways of Quercetin in Tubular Cells: Involvement of Its Antioxidant Properties in the Kidney

Abstract

Quercetin is a flavonoid with antioxidant, antiviral, antimicrobial, and anti-inflammatory properties. Therefore, it has been postulated as a molecule with great therapeutic potential. The renoprotective capacity of quercetin against various toxins that produce oxidative stress, in both in vivo and in vitro models, has been shown. However, it is not clear whether quercetin itself or any of its metabolites are responsible for the protective effects on the kidney. Although the pharmacokinetics of quercetin have been widely studied and the complexity of its transit throughout the body is well known, the metabolic processes that occur in the kidney are less known. Because of that, the objective of this review was to delve into the molecular and cellular events triggered by quercetin and/or its metabolites in the tubular cells, which could explain some of the protective properties of this flavonoid against oxidative stress produced by toxin administration. Thus, the following are analyzed: (1) the transit of quercetin to the kidney; (2) the uptake mechanisms of quercetin and its metabolites from plasma to the tubular cells; (3) the metabolic processes triggered in those cells, which affect the accumulation of metabolites in the intracellular space; and (4) the efflux mechanisms of these compounds and their subsequent elimination through urine. Finally, it is discussed whether those processes that are mediated in the tubular cells and that give rise to different metabolites are related to the antioxidant and renoprotective properties observed after the administration of quercetin.

Protective Effect of Quercetin 3-O-Glucuronide against Cisplatin Cytotoxicity in Renal Tubular Cells

“…After i.p. administration, metabolism in enterocytes does not take place [12], while a first-pass effect occurs via p.o., with the compound being biotransformed before entering systemic circulation [26]. Therefore, the nephroprotection of quercetin against cisplatin could be related to the concentrations reached in the kidney by quercetin itself or its metabolites, which could be different depending on the administration route of the flavonoid.…”

“…Thus, it can be speculated that the use of quercetin 3'-O-glucuronide might still improve the cytoprotective effect observed for quercetin 3-O-glucuronide in the present work. It has also been suggested that these metabolites could be involved in the induction of antioxidant defense mechanisms through inducing the expression of antioxidant enzymes [12]. In addition, some published studies have demonstrated therapeutic effects of glucuronide metabolites [30,31].…”

“…However, quercetin glycosides are present in human urine samples after ingesting foods rich in quercetin, whereas they are not present in plasma. This implies that they are formed in the kidney in situ based on local metabolism [12]. It should not be ruled out that glycosides are involved in nephroprotection, perhaps by action on other renal cells.…”

“…In natural media, quercetin is usually found in glycosylated form. Quercetin glycosides can be partially hydrolyzed in saliva [11] and further in the small intestine by the enzyme lactase-phlorizin hydrolase in the intestinal epithelium releasing the aglycone that may be subsequently absorbed [12]. Efficient glucuronidation of quercetin can already occur in the small intestine by the action of UDP-glucuronyltransferases, as well as methylation by the action of catechol O-methyltransferases.…”

“…Tubular cells have the enzymatic capacity to carry out a third biotransformation of quercetin. The metabolic conversions that occur include a complex combination of metabolite deconjugation followed by immediate sulfation, glucuronidation, methylation, and glucosylation [12].…”