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

Abstract

Quercetin, a flavonoid with promising therapeutic potential, has been shown to protect from cisplatin nephrotoxicity in rats following intraperitoneal injection, but its low bioavailability curtails its prospective clinical utility in oral therapy. We recently developed a micellar formulation (P-quercetin) with enhanced solubility and bioavailability, and identical nephroprotective properties. As a first aim, we herein evaluated the oral treatment with P-quercetin in rats, which displayed no nephroprotection. In order to unravel this discrepancy, quercetin and its main metabolites were measured by HPLC in the blood and urine after intraperitoneal and oral administrations. Whilst quercetin was absorbed similarly, the profile of its metabolites was different, which led us to hypothesize that nephroprotection might be exerted in vivo by a metabolic derivate. Consequently, we then aimed to evaluate the cytoprotective capacity of quercetin and its main metabolites (quercetin 3-O-glucoside, rutin, tamarixetin, isorhamnetin and quercetin 3-O-glucuronide) against cisplatin toxicity, in HK-2 and NRK-52E tubular cell lines. Cells were incubated for 6 h with quercetin, its metabolites or vehicle (pretreatment), and subsequently 18 h in cotreatment with 10–300 μM cisplatin. Immediately after treatment, cell cultures were subject to the MTT technique as an index of cytotoxicity and photographed under light microscopy for phenotypic assessment. Quercetin afforded no direct cytoprotection and quercetin-3-O-glucuronide was the only metabolite partially preventing the effect of cisplatin in cultured tubule cells. Our results identify a metabolic derivative of quercetin contributing to its nephroprotection and prompt to further explore exogenous quercetin-3-O-glucuronide in the prophylaxis of tubular nephrotoxicity.

LC-MS/MS and GC-MS Identification of Metabolites from the Selected Herbs and Spices, Their Antioxidant, Anti-Diabetic Potential, and Chemometric Analysis

“…Quercetin 3 -O-glucuronide has potent antioxidant and anti-inflammatory properties, immune-boosting properties, and potential therapeutic effects in the treatment of diabetes [71]. It may also have unique benefits in improving exercise performance and recovery and protecting the liver against damage caused by toxins [72] ) at m/z 609.1466 in mint leaves. Isorhamnetin has potent anti-cancer and anti-inflammatory properties, cardiovascular benefits, reduced inflammation and oxidative stress, and improved blood pressure and cholesterol levels.…”

Quercetin Alleviates Toxicity Induced by High Levels of Copper in Porcine Follicular Granulosa Cells by Scavenging Reactive Oxygen Species and Improving Mitochondrial Function

“…It has been reported that QUE protects granulosa cells from damage caused by oxidative stress in pigs [25], goats [57], buffaloes [28], and chickens [58]. Moreover, QUE alleviates the toxic effects of heavy metals such as copper [59], cadmium [60], cisplatin [61], iron [62], and lead [63]. And a physiological dose of QUE could remove ROS and effectively reverse the decrease in MMP [64][65][66], thus exerting its antioxidant effect to protect cells.…”

Pharmacological Activity of Quercetin: An Updated Review

“…Quercetin exerts beneficial effects on type 2 diabetes potentially by inhibiting pancreatic iron deposition and pancreatic β cells ferroptosis [ 94 ]. Quercetin-3-O-glucuronide is a metabolite of quercetin that has been shown to block the role of renal platinum in tubular cells and can prevent tubular toxicity and play a renal protective role [ 95 ].…”