Inhibitory Effects of Quercetin and Its Human and Microbial Metabolites on Xanthine Oxidase Enzyme

Abstract

Quercetin is an abundant flavonoid in nature and is used in several dietary supplements. Although quercetin is extensively metabolized by human enzymes and the colonic microflora, we have only few data regarding the pharmacokinetic interactions of its metabolites. Therefore, we investigated the interaction of human and microbial metabolites of quercetin with the xanthine oxidase enzyme. Inhibitory effects of five conjugates and 23 microbial metabolites were examined with 6-mercaptopurine and xanthine substrates (both at 5 μM), employing allopurinol as a positive control. Quercetin-3′-sulfate, isorhamnetin, tamarixetin, and pyrogallol proved to be strong inhibitors of xanthine oxidase. Sulfate and methyl conjugates were similarly strong inhibitors of both 6-mercaptopurine and xanthine oxidations (IC50 = 0.2–0.7 μM); however, pyrogallol inhibited xanthine oxidation (IC50 = 1.8 μM) with higher potency vs. 6-MP oxidation (IC50 = 10.1 μM). Sulfate and methyl conjugates were approximately ten-fold stronger inhibitors (IC50 = 0.2–0.6 μM) of 6-mercaptopurine oxidation than allopurinol (IC50 = 7.0 μM), and induced more potent inhibition compared to quercetin (IC50 = 1.4 μM). These observations highlight that some quercetin metabolites can exert similar or even a stronger inhibitory effect on xanthine oxidase than the parent compound, which may lead to the development of quercetin–drug interactions (e.g., with 6-mercaptopurin or azathioprine).

Effect of Muntingia calabura L. Stem Bark Extracts on Uric Acid Concentration and Renal Histopathology in Diabetic Rats

“…Flavonoids can reduce uric acid by reducing the activity of xanthine oxidase in serum and increasing the concentration of uric acid in urine and binding free radicals as long as the purine changes into uric acid. Flavonoid can inhibit the performance of xanthine oxidase and xanthine dehydrogenase, so that it can inhibit uric acid synthesis [25,26]. In addition, extract of M calabura stem bark contain triterpenoid and it was reported that triterpenoid and triterpenoid saponin or riparsaponin could significantly inhibit xanthine oxidase activity so that uric acid decreases in the blood [27,28].…”

Interactions of 7,8-Dihydroxyflavone with Serum Albumin as well as with CYP2C9, CYP2C19, CYP3A4, and Xanthine Oxidase Biotransformation Enzymes

“…The inhibitory action of DHF on XO was investigated as described earlier [31]. In the enzyme-catalyzed reaction, 6-mercaptopurine is oxidized to 6-thiouric acid.…”

“…6-mercaptopurine and 6-thiouric acid were quantified as described earlier [31]. The samples were driven through a Phenomenex SecurityGuard (C18, 4.0 × 3.0 mm) guard column linked to a Phenomenex Gemini-NX C18 (150 × 4.6 mm, 3 μm) analytical column.…”

Inhibitory Effects of Quercetin and Its Main Methyl, Sulfate, and Glucuronic Acid Conjugates on Cytochrome P450 Enzymes, and on OATP, BCRP and MRP2 Transporters

“…This hypothesis is supported by the report of Bedada and Neerati [ 67 ] where the administered Q (500 mg twice daily for 10 days) significantly decreased the CYP2C9-mediated elimination of diclofenac in healthy human subjects, despite the observations in a previous in vitro study that Q and some of its conjugates (Q3′S, IR, and tamarixetin) were only weak inhibitors of the enzyme and glucuronides (Q3G and I3G) did not affect CYP2C9 activity [ 14 ]. Previous studies showed the similar or stronger interactions of methyl and sulfate metabolites of Q with xanthine oxidase enzyme [ 68 ] and human serum albumin [ 14 , 69 ] compared to the parent compound. Furthermore, Q sulfates and glucuronides showed potent inhibitory effects on organic anion transporters (OAT1 and OAT3) [ 70 ].…”