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.

Department of Laboratory Medicine Medical School University of Pécs Pécs Hungary

Department of Pharmaceutics and Central Clinical Pharmacy Faculty of Pharmacy University of Pécs Pécs Hungary

Department of Pharmacognosy Faculty of Pharmacy University of Pécs Pécs Hungary

Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

Molecular Medicine Research Group János Szentágothai Research Centre University of Pécs Pécs Hungary

National Laboratory for Drug Research and Development Budapest Hungary

Pharmacoinformatics Unit Department of Pharmacology and Pharmacotherapy Medical School University of Pécs Pécs Hungary

Zobrazit více v PubMed

Musial C, Kuban‐Jankowska A and Gorska‐Ponikowska M, Beneficial properties of green tea catechins. Int J Mol Sci 21:1744 (2020). PubMed PMC

van het Hof KH, Kivits GA, Weststrate JA and Tijburg LB, Bioavailability of catechins from tea: the effect of milk. Eur J Clin Nutr 52:356–359 (1998). 10.1038/sj.ejcn.1600568. PubMed DOI

Widlansky ME, Duffy SJ, Hamburg NM, Gokce N, Warden BA, Wiseman S et al., Effects of black tea consumption on plasma catechins and markers of oxidative stress and inflammation in patients with coronary artery disease. Free Radic Biol Med 38:499–506 (2005). 10.1016/j.freeradbiomed.2004.11.013. PubMed DOI

Khattar S, Khan SA, Zaidi SAA, Darvishikolour M, Farooq U, Naseef PP et al., Resveratrol from dietary supplement to a drug candidate: an assessment of potential. Pharmaceuticals 15:957 (2022). PubMed PMC

Berman AY, Motechin RA, Wiesenfeld MY and Holz MK, The therapeutic potential of resveratrol: a review of clinical trials. NPJ Precis Oncol 1:35 (2017). 10.1038/s41698-017-0038-6. PubMed DOI PMC

Walle T, Bioavailability of resveratrol: resveratrol bioavailability. Ann N Y Acad Sci 1215:9–15 (2011). 10.1111/j.1749-6632.2010.05842.x. PubMed DOI

Yu C, Shin YG, Chow A, Li Y, Kosmeder JW, Lee YS et al., Human, rat, and mouse metabolism of resveratrol. Pharm Res 19:1907–1914 (2002). 10.1023/A:1021414129280. PubMed DOI

Wenzel E, Soldo T, Erbersdobler H and Somoza V, Bioactivity and metabolism of trans‐resveratrol orally administered to Wistar rats. Mol Nutr Food Res 49:482–494 (2005). 10.1002/mnfr.200500003. PubMed DOI

Patel KR, Brown VA, Jones DJL, Britton RG, Hemingway D, Miller AS et al., Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. Cancer Res 70:7392–7399 (2010). 10.1158/0008-5472.CAN-10-2027. PubMed DOI PMC

Boocock DJ, Faust GES, Patel KR, Schinas AM, Brown VA, Ducharme MP et al., Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol Biomarkers Prev 16:1246–1252 (2007). 10.1158/1055-9965.EPI-07-0022. PubMed DOI

Brown VA, Patel KR, Viskaduraki M, Crowell JA, Perloff M, Booth TD et al., Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: safety, pharmacokinetics, and effect on the insulin‐like growth factor axis. Cancer Res 70:9003–9011 (2010). 10.1158/0008-5472.CAN-10-2364. PubMed DOI PMC

Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A and Capasso R, Milk thistle (Silybum marianum): a concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res 32:2202–2213 (2018). 10.1002/ptr.6171. PubMed DOI

Chambers CS, Holeckova V, Petraskova L, Biedermann D, Valentova K, Buchta M et al., The silymarin composition… and why does it matter??? Food Res Int 100:339–353 (2017). 10.1016/j.foodres.2017.07.017. PubMed DOI

Křen V and Valentová K, Silybin and its congeners: from traditional medicine to molecular effects. Nat Prod Rep 39:1264–1281 (2022). 10.1039/d2np00013j. PubMed DOI

Hoh C, Boocock D, Marczylo T, Singh R, Berry DP, Dennison AR et al., Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences. Clin Cancer Res 12:2944–2950 (2006). 10.1158/1078-0432.ccr-05-2724. PubMed DOI

Lněničková K, Vrba J, Kosina P, Papoušková B, Mekadim C, Mrázek J et al., Metabolic profiling of silymarin constituents in urine and feces of healthy volunteers: a 90‐day study. J Funct Food 100:105391 (2023). 10.1016/j.jff.2022.105391. DOI

Brinda BJ, Zhu HJ and Markowitz JS, A sensitive LC–MS/MS assay for the simultaneous analysis of the major active components of silymarin in human plasma. J Chromatogr B 902:1–9 (2012). 10.1016/j.jchromb.2012.06.003. PubMed DOI

Saller R, Meier R and Brignoli R, The use of silymarin in the treatment of liver diseases. Drugs 61:2035–2063 (2001). 10.2165/00003495-200161140-00003. PubMed DOI

He Q, Mok TN, Sin TH, Yin J, Li S, Yin Y et al., Global, regional, and national prevalence of gout from 1990 to 2019: age‐period‐cohort analysis with future burden prediction. JMIR Public Health Surveill 9:e45943 (2023). 10.2196/45943. PubMed DOI PMC

Yang S, Liu H, Fang XM, Yan F and Zhang Y, Signaling pathways in uric acid homeostasis and gout: from pathogenesis to therapeutic interventions. Int Immunopharmacol 132:111932 (2024). PubMed

Schmidt HM, Kelley EE and Straub AC, The impact of xanthine oxidase (XO) on hemolytic diseases. Redox Biol 21:101072 (2019). PubMed PMC

Harrison R, Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med 33:774–797 (2002). 10.1016/s0891-5849(02)00956-5. PubMed DOI

Berry CE and Hare JM, Xanthine oxidoreductase and cardiovascular disease: molecular mechanisms and pathophysiological implications. J Physiol 555:589–606 (2004). 10.1113/jphysiol.2003.055913. PubMed DOI PMC

Galbusera C, Orth P, Fedida D and Spector T, Superoxide radical production by allopurinol and xanthine oxidase. Biochem Pharmacol 71:1747–1752 (2006). 10.1016/j.bcp.2006.02.008. PubMed DOI

Mehmood A, Ishaq M, Zhao L, Safdar B, Rehman A, Munir M et al., Natural compounds with xanthine oxidase inhibitory activity: a review. Chem Biol Drug Des 93:387–418 (2019). 10.1111/cbdd.13437. PubMed DOI

Naeem A, Ming Y, Pengyi H, Jie KY, Yali L, Haiyan Z et al., The fate of flavonoids after oral administration: a comprehensive overview of its bioavailability. Crit Rev Food Sci Nutr 62:6169–6186 (2022). 10.1080/10408398.2021.1898333. PubMed DOI

Mohos V, Pánovics A, Fliszár‐Nyúl E, Schilli G, Hetényi C, Mladěnka P et al., Inhibitory effects of quercetin and its human and microbial metabolites on xanthine oxidase enzyme. Int J Mol Sci 20:2681 (2019). PubMed PMC

Balázs O, Dombi Á, Zsidó BZ, Hetényi C, Valentová K, Vida RG et al., Inhibition of xanthine oxidase‐catalyzed xanthine and 6‐mercaptopurine oxidation by luteolin, naringenin, myricetin, ampelopsin and their conjugated metabolites. Biomed Pharmacother 167:115548 (2023). PubMed

Yuan M, Liu Y, Xiao A, Leng J, Liao L, Ma L et al., The interaction of dietary flavonoids with xanthine oxidase in vitro: molecular property‐binding affinity relationship aspects. RSC Adv 9:10781–10788 (2019). 10.1039/c8ra09926j. PubMed DOI PMC

Rashidinejad A, Birch EJ and Everett DW, Green tea catechins suppress xanthine oxidase activity in dairy products: an improved HPLC analysis. J Food Compos Anal 48:120–127 (2016). 10.1016/j.jfca.2016.03.001. DOI

Zhang G, Zhu M, Liao Y, Gong D and Hu X, Action mechanisms of two key xanthine oxidase inhibitors in tea polyphenols and their combined effect with allopurinol. J Sci Food Agric 102:7195–7208 (2022). 10.1002/jsfa.12085. PubMed DOI

Huang XF, Li HQ, Shi L, Xue JY, Ruan BF and Zhu HL, Synthesis of resveratrol analogues, and evaluation of their cytotoxic and xanthine oxidase inhibitory activities. Chem Biodivers 5:636–642 (2008). 10.1002/cbdv.200890059. PubMed DOI

Agbadua OG, Kúsz N, Berkecz R, Gáti T, Tóth G and Hunyadi A, Oxidized resveratrol metabolites as potent antioxidants and xanthine oxidase inhibitors. Antioxidants 11:1832 (2022). PubMed PMC

Varga Z, Seres I, Nagy E, Ujhelyi L, Balla G, Balla J et al., Structure prerequisite for antioxidant activity of silybin in different biochemical systems in vitro. Phytomedicine 13:85–93 (2006). 10.1016/j.phymed.2004.06.019. PubMed DOI

Pauff JM and Hille R, Inhibition studies of bovine xanthine oxidase by luteolin, silibinin, quercetin, and curcumin. J Nat Prod 72:725–731 (2009). 10.1021/np8007123. PubMed DOI PMC

Mottet C, Schoepfer AM, Juillerat P, Cosnes J, Froehlich F, Kessler‐Brondolo V et al., Experts opinion on the practical use of azathioprine and 6‐mercaptopurine in inflammatory bowel disease. Inflamm Bowel Dis 22:2733–2747 (2016). 10.1097/MIB.0000000000000923. PubMed DOI

McLeod HL, Clinically relevant drug‐drug interactions in oncology. Br J Clin Pharm 45:539–544 (1998). 10.1046/j.1365-2125.1998.00719.x. PubMed DOI PMC

Valentová K, Purchartová K, Rydlová L, Roubalová L, Biedermann D, Petrásková L et al., Sulfated metabolites of flavonolignans and 2,3‐dehydroflavonolignans: preparation and properties. Int J Mol Sci 19:2349 (2018). PubMed PMC

Faisal Z, Mohos V, Fliszár‐Nyúl E, Valentová K, Káňová K, Lemli B et al., Interaction of silymarin components and their sulfate metabolites with human serum albumin and cytochrome P450 (2C9, 2C19, 2D6, and 3A4) enzymes. Biomed Pharmacother 138:111459 (2021). PubMed

Balázs O, Dombi Á, Zsidó BZ, Hetényi C, Vida RG and Poór M, Probing the interactions of 31 mycotoxins with xanthine oxidase: alternariol, alternariol‐3‐sulfate, and α‐zearalenol are allosteric inhibitors of the enzyme. Toxins 15:250 (2023). PubMed PMC

Hu T and Liu Y, Probing the interaction of cefodizime with human serum albumin using multi‐spectroscopic and molecular docking techniques. J Pharm Biomed Anal 107:325–332 (2015). 10.1016/j.jpba.2015.01.010. PubMed DOI

Wang T, Zeng LH and Li DL, A review on the methods for correcting the fluorescence inner‐filter effect of fluorescence spectrum. Appl Spectrosc Rev 52:883–908 (2017). 10.1080/05704928.2017.1345758. DOI

Najaran A, Divsalar A, Saboury AA and Roodbari NH, Probing the interaction of newly synthesized Pt(II) complex on human serum albumin using competitive binding site markers. J Fluoresc 29:827–835 (2019). 10.1007/s10895-019-02383-3. PubMed DOI

Mohammadgholi A, Leilabadi‐Asl A, Divsalar A and Eslami‐Moghadam M, Multi‐spectroscopic studies of the interaction of new synthesized platin complex with human carrier protein of serum albumin. J Biomol Struct Dyn 39:1506–1511 (2021). 10.1080/07391102.2020.1745690. PubMed DOI

Chaves OA, dos Santos Oliveira CHC, Ferreira RC, Cesarin‐Sobrinho D, da Hora Machado AE and Netto‐Ferreira JC, Synthetic dimethoxyxanthones bind similarly to human serum albumin compared with highly oxygenated xanthones. Chem Phys Impact 8:100411 (2024).

Mohos V, Fliszár‐Nyúl E, Lemli B, Zsidó BZ, Hetényi C, Mladěnka P et al., Testing the pharmacokinetic interactions of 24 colonic flavonoid metabolites with human serum albumin and cytochrome P450 enzymes. Biomolecules 10:409 (2020). PubMed PMC

Csenki Z, Bartók T, Bock I, Horváth L, Lemli B, Zsidó BZ et al., Interaction of fumonisin B1, N‐palmitoyl‐fumonisin B1, 5‐O‐palmitoyl‐fumonisin B1, and fumonisin B4 mycotoxins with human serum albumin and their toxic impacts on zebrafish embryos. Biomolecules 13:755 (2023). PubMed PMC

Pauff JM, Cao H and Hille R, Substrate orientation and catalysis at the molybdenum site in xanthine oxidase. J Biol Chem 284:8760–8767 (2009). 10.1074/jbc.M804517200. PubMed DOI PMC

Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK et al., Automated docking using a Lamarckian genetic algorithm and empirical binding free energy function. J Comput Chem 19:1639–1662 (1998). 10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B. DOI

Zsidó BZ, Börzsei R, Szél V and Hetényi C, Determination of ligand binding modes in hydrated viral ion channels to foster drug design and repositioning. J Chem Inf Model 61:4011–4022 (2021). 10.1021/acs.jcim.1c00488. PubMed DOI PMC

Zsidó BZ, Balog M, Erős N, Poór M, Mohos V, Fliszár‐Nyúl E et al., Synthesis of spin‐labelled bergamottin: a potent CYP3A4 inhibitor with antiproliferative activity. Int J Mol Sci 21:508 (2020). PubMed PMC

Mahomoodally MF, Coodian K, Hosenally M, Zengin G, Shariati MA, Abdalla AN et al., Herbal remedies in the management of hyperuricemia and gout: a review of in vitro, in vivo and clinical evidences. Phytother Res 38:3370–3400 (2024). 10.1002/ptr.8211. PubMed DOI

Mohos V, Fliszár‐Nyúl E and Poór M, Inhibition of xanthine oxidase‐catalyzed xanthine and 6‐mercaptopurine oxidation by flavonoid aglycones and some of their conjugates. Int J Mol Sci 21:3256 (2020). PubMed PMC

Petrásková L, Káňová K, Biedermann D, Křen V and Valentová K, Simple and rapid HPLC separation and quantification of flavonoid, flavonolignans, and 2,3‐dehydroflavonolignans in silymarin. Foods 9:116 (2020). PubMed PMC

Tvrdý V, Pourová J, Jirkovský E, Křen V, Valentová K and Mladěnka P, Systematic review of pharmacokinetics and potential pharmacokinetic interactions of flavonolignans from silymarin. Med Res Rev 41:2195–2246 (2021). 10.1002/med.21791. PubMed DOI