BACKGROUND: Over the past two decades, the global incidence of gout has markedly increased, affecting people worldwide. Considering the side effects of xanthine oxidase (XO) inhibitor drugs (e.g. allopurinol and febuxostat) used in the treatment of hyperuricemia and gout, the potential application of phytochemicals has been widely studied. In addition, XO also takes part in the elimination of certain drugs, including 6-mercaptopurine. In the current explorative study, we aimed to examine the potential effects of tea catechins, resveratrol, silymarin flavonolignans and some of their conjugated metabolites on XO-catalyzed xanthine and 6-mercaptopurine oxidation, applying in vitro assays and modeling studies. RESULTS: Catechins, resveratrol and resveratrol conjugates exerted no or only weak inhibitory effects on XO. Silybin A, silybin B and isosilybin A were weak, silychristin was a moderate, while 2,3-dehydrosilychristin was a potent inhibitor of the enzyme. Sulfate metabolites of silybin A, silybin B and isosilybin A were considerably stronger inhibitors compared to the parent flavonolignans, and the sulfation of 2,3-dehydrosilychristin slightly increased its inhibitory potency. Silychristin was the sole flavonolignan tested, where sulfate conjugation decreased its inhibitory effect. CONCLUSION: 2,3-Dehydrosilychristin seems to be a promising candidate for examining its in vivo antihyperuricemic effects, because both the parent compound and its sulfate conjugate are highly potent inhibitors of XO. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

• Klíčová slova
• catechins, enzyme inhibition, resveratrol, silymarin, sulfate conjugates, xanthine oxidase,
• MeSH
• inhibitory enzymů chemie   MeSH
• katalýza MeSH
• katechin * chemie   MeSH
• lidé MeSH
• merkaptopurin * chemie   metabolismus   MeSH
• oxidace-redukce MeSH
• resveratrol * chemie   MeSH
• silibinin chemie   MeSH
• silymarin * chemie   MeSH
• xanthin * chemie   metabolismus   MeSH
• xanthinoxidasa * chemie   metabolismus   antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory enzymů MeSH
• katechin * MeSH
• merkaptopurin * MeSH
• resveratrol * MeSH
• silibinin MeSH
• silymarin * MeSH
• xanthin * MeSH
• xanthinoxidasa * MeSH

Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs.

• Klíčová slova
• CYP450 enzymes, O-desmethylangolensin, colonic flavonoid metabolites, pharmacokinetic interaction, phloroglucinol, polyphenols, resorcinol, serum albumin,
• MeSH
• erytrocyty enzymologie   MeSH
• flavonoidy * chemie   metabolismus   MeSH
• hepatocyty enzymologie   MeSH
• lidé MeSH
• lidský sérový albumin * chemie   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 * chemie   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• flavonoidy * MeSH
• lidský sérový albumin * MeSH
• systém (enzymů) cytochromů P-450 * MeSH