Inhibition of xanthine oxidase-catalyzed xanthine and 6-mercaptopurine oxidation by luteolin, naringenin, myricetin, ampelopsin and their conjugated metabolites

Orsolya Balázs; Ágnes Dombi; Balázs Z Zsidó; Csaba Hetényi; Kateřina Valentová; Róbert G Vida; Miklós Poór

doi:10.1016/j.biopha.2023.115548

Inhibition of xanthine oxidase-catalyzed xanthine and 6-mercaptopurine oxidation by luteolin, naringenin, myricetin, ampelopsin and their conjugated metabolites

Biomed Pharmacother. 2023 Nov:167:115548. doi: 10.1016/j.biopha.2023.115548. Epub 2023 Sep 19.

Authors

Orsolya Balázs¹, Ágnes Dombi², Balázs Z Zsidó³, Csaba Hetényi³, Kateřina Valentová⁴, Róbert G Vida⁵, Miklós Poór⁶

Affiliations

¹ Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary; Department of Pharmaceutics and Central Clinical Pharmacy, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary.
² Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary.
³ Unit of Pharmacoinformatics, Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, H-7624 Pécs, Hungary.
⁴ Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ-142 00 Prague, Czech Republic.
⁵ Department of Pharmaceutics and Central Clinical Pharmacy, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary.
⁶ Department of Pharmacology, Faculty of Pharmacy, University of Pécs, Rókus u. 2, H-7624 Pécs, Hungary. Electronic address: poor.miklos@pte.hu.

PMID: 37734263
DOI: 10.1016/j.biopha.2023.115548

Abstract

Luteolin, naringenin, myricetin, and ampelopsin are abundant flavonoids in nature, and several dietary supplements also contain them at very high doses. After the peroral intake, flavonoids go through extensive presystemic biotransformation; therefore, typically their sulfate/glucuronic acid conjugates reach high concentrations in the circulation. Xanthine oxidase (XO) enzyme is involved in uric acid production, and it also takes part in the elimination of certain drugs (e.g., 6-mercaptopurine). The inhibitory effects of flavonoid aglycones on XO have been widely studied; however, only limited data are available regarding their sulfate and glucuronic acid conjugates. In this study, we examined the impacts of luteolin, naringenin, myricetin, ampelopsin, and their sulfate/glucuronide derivatives on XO-catalyzed xanthine and 6-mercaptopurine oxidations employing in vitro enzyme incubation assays and molecular modeling studies. Our major results/conclusions are the following: (1) Sulfate metabolites were stronger while glucuronic acid derivatives were weaker inhibitors of XO compared to the parent flavonoids. (2) Naringenin, ampelopsin, and their metabolites were weak inhibitors of the enzyme. (3) Luteolin, myricetin, and their sulfates were highly potent inhibitors of XO, and the glucuronides of luteolin showed moderate inhibitory impacts. (4) Conjugated metabolites of luteolin and myricetin can be involved in the inhibitory effects of these flavonoids on XO enzyme.

Keywords: Ampelopsin; Flavonoid conjugates; Luteolin; Myricetin; Naringenin; Xanthine oxidase.