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.

• Keywords
• catechins, enzyme inhibition, resveratrol, silymarin, sulfate conjugates, xanthine oxidase,
• MeSH
• Enzyme Inhibitors chemistry   MeSH
• Catalysis MeSH
• Catechin * chemistry   MeSH
• Humans MeSH
• Mercaptopurine * chemistry   metabolism   MeSH
• Oxidation-Reduction MeSH
• Resveratrol * chemistry   MeSH
• Silybin chemistry   MeSH
• Silymarin * chemistry   MeSH
• Xanthine * chemistry   metabolism   MeSH
• Xanthine Oxidase * chemistry   metabolism   antagonists & inhibitors   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Enzyme Inhibitors MeSH
• Catechin * MeSH
• Mercaptopurine * MeSH
• Resveratrol * MeSH
• Silybin MeSH
• Silymarin * MeSH
• Xanthine * MeSH
• Xanthine Oxidase * MeSH

Myricetin (MYR) and ampelopsin (AMP, or dihydromyricetin) are flavonoid aglycones found in certain plants and dietary supplements. During the presystemic biotransformation of flavonoids, mainly sulfate and glucuronide derivatives are produced, which are the dominant metabolites in the circulation. In this study, we tested the interactions of MYR, myricetin-3'-O-sulfate (M3'S), AMP, and ampelopsin-4'-O-sulfate (A4'S) with human serum albumin (HSA), cytochrome P450 enzymes (CYPs), and organic anion-transporting polypeptides (OATPs) using in vitro models, including the recently developed method for measuring flavonoid levels in living cells. M3'S and MYR bound to albumin with high affinity, and they showed moderate displacing effects versus the Site I marker warfarin. MYR, M3'S, AMP, and A4'S exerted no or only minor inhibitory effects on CYP2C9, CYP2C19, and CYP3A4 enzymes. M3'S and MYR caused considerable inhibitory actions on OATP1B1 at low micromolar concentrations (IC50 = 1.7 and 6.4 μM, respectively), while even their nanomolar levels resulted in strong inhibitory effects on OATP2B1 (IC50 = 0.3 and 0.4 μM, respectively). In addition, M3'S proved to be a substrate of OATP1B1 and OATP2B1. These results suggest that MYR-containing dietary supplements may affect the OATP-mediated transport of certain drugs, and OATPs are involved in the tissue uptake of M3'S.

• Keywords
• CYP enzymes, OATP transporters, ampelopsin, human serum albumin, myricetin,
• MeSH
• Cytochrome P-450 CYP3A metabolism   MeSH
• Cytochrome P-450 CYP2C9 metabolism   MeSH
• Flavonoids * pharmacology   MeSH
• Flavonols pharmacology   MeSH
• Humans MeSH
• Liver-Specific Organic Anion Transporter 1 * metabolism   MeSH
• Organic Anion Transporters * metabolism   MeSH
• Serum Albumin metabolism   MeSH
• Sulfates metabolism   MeSH
• Cytochrome P-450 Enzyme System metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ampelopsin MeSH Browser
• CYP3A4 protein, human MeSH Browser
• Cytochrome P-450 CYP3A MeSH
• Cytochrome P-450 CYP2C9 MeSH
• dihydromyricetin MeSH Browser
• Flavonoids * MeSH
• Flavonols MeSH
• myricetin MeSH Browser
• Liver-Specific Organic Anion Transporter 1 * MeSH
• Organic Anion Transporters * MeSH
• Serum Albumin MeSH
• Sulfates MeSH
• SLCO1B1 protein, human MeSH Browser
• SLCO2B1 protein, human MeSH Browser
• Cytochrome P-450 Enzyme System MeSH