{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:56:45Z","timestamp":1782939405492,"version":"3.54.5"},"reference-count":56,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,2]],"date-time":"2018-03-02T00:00:00Z","timestamp":1519948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb\u2013drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 \u03bcM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone\u2013drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.<\/jats:p>","DOI":"10.3390\/molecules23030555","type":"journal-article","created":{"date-parts":[[2018,3,2]],"date-time":"2018-03-02T11:53:40Z","timestamp":1519991620000},"page":"555","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone"],"prefix":"10.3390","volume":"23","author":[{"given":"Eun","family":"Gong","sequence":"first","affiliation":[{"name":"College of Pharmacy and Intergrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya","family":"Chea","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Intergrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Balupuri","sequence":"additional","affiliation":[{"name":"Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam","family":"Kang","sequence":"additional","affiliation":[{"name":"Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Won","family":"Chin","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Intergrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9360-6436","authenticated-orcid":false,"given":"Young","family":"Choi","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Intergrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang, Gyeonggi-do 10326, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1007\/s12272-011-1106-z","article-title":"Herb-drug interactions: Focus on metabolic enzymes and transporters","volume":"34","author":"Choi","year":"2011","journal-title":"Arch. Pharm. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.2165\/11317010-000000000-00000","article-title":"Interactions between herbal medicines and prescribed drugs: An updated systemic review","volume":"69","author":"Izzo","year":"2009","journal-title":"Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.jep.2016.06.039","article-title":"Flavokawain A inhibits cytochrome P450 in in vitro metabolic and inhibitory investigations","volume":"191","author":"Niu","year":"2016","journal-title":"J. Ethnopharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.phymed.2017.05.002","article-title":"In vitro inhibitory mechanisms and molecular docking of 1\u2032-S-1\u2032-acetoxychavicol acetate on human cytochrome P450 enzymes","volume":"31","author":"Haque","year":"2017","journal-title":"Phytomedicine"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"791","DOI":"10.2174\/1389200216666150223152348","article-title":"Pharmacokinetic interactions between herbal medicines and prescribed drugs: Focus on drug metabolic enzymes and transporters","volume":"15","author":"Meng","year":"2014","journal-title":"Curr. Drug Metab."},{"key":"ref_6","first-page":"66","article-title":"The role of metabolites in predicting drug-drug interactions: Focus on irreversible cytochrome P450 inhibition","volume":"13","author":"Isoherranen","year":"2010","journal-title":"Curr. Opin. Drug Discov. Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.jep.2014.07.026","article-title":"Mulrifaced interation of the traditional chinese medical herb Schisandra chinesis with cytochrome P450-mediated drug metabolism in rats","volume":"155","author":"Wang","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"599","DOI":"10.2174\/1389200211209050599","article-title":"Interactions between phytochemicals from traditional Chinese medicines and human cytochrome P450 enzymes","volume":"13","author":"Wu","year":"2012","journal-title":"Curr. Drug Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.ctrv.2012.12.008","article-title":"Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb-drug interactions in cancer patients","volume":"39","author":"Goey","year":"2013","journal-title":"Caner Treat. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1055\/s-0032-1315117","article-title":"Clinical evidence of herbal drugs as perpetrators of pharmacokinetic drug interactions","volume":"78","author":"Hermann","year":"2012","journal-title":"Planta Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1097\/FJC.0b013e3181ffe8d0","article-title":"The effect of St John\u2019s Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: Increased platelet inhibition by enhancement of CYP3A4 metabolic activity","volume":"57","author":"Lau","year":"2011","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_12","first-page":"289","article-title":"Cranberry juice ingestion and clinical drug-drug interaction potentials: Review of case studies and perspectives","volume":"16","author":"Srinivas","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1007\/s13181-015-0465-0","article-title":"A review of the toxicity of HIV medications II: Interactions with drugs and complementary and alternative medicine products","volume":"11","author":"Stolbach","year":"2015","journal-title":"J. Med. Toxicol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1124\/dmd.109.026716","article-title":"The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: A prospective of the pharmaceutical research and manufacturers of America","volume":"37","author":"Grimm","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_15","unstructured":"Food and Drug Adminstration (2012). Guidance for Industry-Drug Interaction Studies-Study Design, Data Analysis, Implications for Dosing and Labeling, Food and Drug Adminstration."},{"key":"ref_16","unstructured":"Chung, B.S., and Shin, M.G. (1990). Dictionary of Korean Folk Medicine, Young Lim Sa."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kim, H.-B., Hwang, E.-S., Choi, G.-Y., Lee, S., Park, T.-S., Lee, C.-W., Lee, E.-S., Kim, Y.-C., Kim, S.S., and Lee, S.-O. (2016). ESP-102, a combined herbal extract of Angelica gigas, Saururus chinensis, and Schisandra chinensis, changes synaptic plasticity and attenuates scopolamine-induced memory impairment in rat hippocampus tissue. Evid.-Based Complement. Altern. Med., 2016.","DOI":"10.1155\/2016\/8793095"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.freeradbiomed.2009.12.006","article-title":"Inhibition of SREBP-1c-mediated hepatic steatosis and oxidative stress by sauchinone, an AMPK-activating lignan in saururus chinensis","volume":"48","author":"Kim","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_19","first-page":"413","article-title":"The hypoglycemic effect of Saururus chinensis Baill in animal models of diabetes mellitus","volume":"15","author":"Joo","year":"2006","journal-title":"Food Sci. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1248\/bpb.34.575","article-title":"Sauchinone attenuated oxidative stress-induced skeletal muscle myoblast damage through the down-regulation of ceramide","volume":"34","author":"Jung","year":"2011","journal-title":"Biol. Pharm. Bull."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1080\/14786410701590657","article-title":"Effects of ethanol extract from Saururus chinensis (Bour.) Baill on lipid and antioxidant metabolisms in rats fed a high-fat diet","volume":"22","author":"Yu","year":"2008","journal-title":"Nat. Prod. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1089\/jmf.2006.149","article-title":"Lipid-lowering effect of hot water-soluble extracts of Saururus chinensis Bail on rats fed high fat diets","volume":"10","author":"Yun","year":"2007","journal-title":"J. Med. Food"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1248\/bpb.b14-00524","article-title":"Pharmacokinetics, tissue distribution, and tentative metabolite identification of sauchinone in mice by microsampling and HPLC-MS\/MS methods","volume":"38","author":"Kim","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, N., Zou, D., and Qiao, H.L. (2013). Concentration-dependent inhibitory effect of baicalin on the plasma protein binding and metabolism of chlorzoxazone, a CYP2E1 probe substrate, in rats in vitro and in vivo. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053038"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s12272-010-0212-7","article-title":"Enantioselective pharmacokinetics of sibutramine in rat","volume":"33","author":"Noh","year":"2010","journal-title":"Arch. Pharm. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/j.1476-5381.2010.00881.x","article-title":"Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro","volume":"161","author":"Zahno","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"28482","DOI":"10.1038\/srep28482","article-title":"Evaluation of the inhibition potential of plumbagin aginst cytochrome P450 using LC-MS\/MS and cocktail approach","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1208\/s12248-008-9042-7","article-title":"In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: Current status on methodologies and their utility for predicting drug-drug interactions","volume":"10","author":"Fowler","year":"2008","journal-title":"AAPS J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2174\/187231208783478407","article-title":"An examination of IC50 and IC50-shift experiments in assessing time-dependent inhibition of CYP3A4, CYP2D6, and CYP2C9 in human liver microsomes","volume":"2","author":"Berry","year":"2008","journal-title":"Drug Metab. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1124\/dmd.114.057695","article-title":"In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors","volume":"42","author":"Filppula","year":"2014","journal-title":"Drug Metab. Dispos."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1124\/dmd.32.6.587","article-title":"Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits major hepatic glucuronosyltransferases","volume":"32","author":"Sridar","year":"2004","journal-title":"Drug Metab. Dispos."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Thomford, N.E., Dzobo, K., Chopera, D., Wonkam, A., Maroyi, A., Blackhurst, D., and Dandara, C. (2016). In vitro reversible and time-dependent CYP450 inhibition profiles of medicinal herbal plant extracts Newbouldia laevis and Cassia abbreviata: Implications for herb-drug interactions. Molecules, 21.","DOI":"10.3390\/molecules21070891"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1002\/jat.1720","article-title":"Direct and metabolism-dependent cytochrome P450 inhibition assays for evaluating drug-drug interactions","volume":"33","author":"Lee","year":"2013","journal-title":"J. Appl. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13682","DOI":"10.1073\/pnas.0603236103","article-title":"Structural basis for ligand promiscuity in cytochrome P450 3A4","volume":"103","author":"Ekroos","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","first-page":"841","article-title":"Estimation of the binding modes with important human cytochrome P450 enzymes, drug interaction potential, pharmacokinetics, and hepatotoxicity of ginger components using molecular docking, computational, and pharmacokinetic modeling studies","volume":"9","author":"Qiu","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3510","DOI":"10.1074\/jbc.M111.317081","article-title":"Structural and mechanistic insights into the interaction of cytochrome P4503A4 with bromoergocryptine, a type I ligand","volume":"287","author":"Sevrioukova","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.phymed.2012.09.021","article-title":"Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes","volume":"20","author":"Zhou","year":"2013","journal-title":"Phytomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1124\/mol.109.062570","article-title":"Crystal structure of a cytochrome P450 2B6 genetic variant in complex with the inhibitor 4-(4-chlorophenyl) imidazole at 2.0-\u00c5 resolution","volume":"77","author":"Gay","year":"2010","journal-title":"Mol. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kobayashi, K., Takahashi, O., Hiratsuka, M., Yamaotsu, N., Hirono, S., Watanabe, Y., and Oda, A. (2014). Evaluation of influence of single nucleotide polymorphisms in cytochrome P450 2B6 on substrate recognition using computational docking and molecular dynamics simulation. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096789"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1007\/s00894-011-0970-2","article-title":"Analysis of clinically relevant substrates of CYP2B6 enzyme by computational methods","volume":"17","author":"Niu","year":"2011","journal-title":"J. Mol. Model."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1021\/jm201346g","article-title":"Ligand-based design of a potent and selective inhibitor of cytochrome P450 2C19","volume":"55","author":"Foti","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"44581","DOI":"10.1074\/jbc.M112.424895","article-title":"Structural Characterization of Human Cytochrome P450 2C19 active site differences between P450s 2C8, 2C9, and 2C19","volume":"287","author":"Reynald","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1002\/bip.22567","article-title":"Molecular basis of the recognition of arachidonic acid by cytochrome P450 2E1 along major access tunnel","volume":"103","author":"Cui","year":"2015","journal-title":"Biopolymers"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jmgm.2014.11.013","article-title":"Structural basis for cooperative binding of azoles to CYP2E1 as interpreted through guided molecular dynamics simulations","volume":"56","author":"Levy","year":"2015","journal-title":"J. Mol. Graph. Model."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"22282","DOI":"10.1074\/jbc.M110.109017","article-title":"Human cytochrome P450 2E1 structures with fatty acid analogs reveal a previously unobserved binding mode","volume":"285","author":"Porubsky","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"198","DOI":"10.6026\/97320630003198","article-title":"Pharmacovigilance: Effects of herbal components on human drugs interactions involving Cytochrome P450","volume":"3","author":"Saxena","year":"2008","journal-title":"Bioinformation"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1002\/bdd.1918","article-title":"Effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel in rats","volume":"36","author":"Chen","year":"2015","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"You, B.H., Gong, E.C., and Choi, Y.H. (2018). Inhibitory Effect of sauchinone on UDP-glucuronosyltransferase (UGT) 2B7 activity. Molecules, 23.","DOI":"10.3390\/molecules23020366"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ejps.2004.10.006","article-title":"Multiple P450 substrates in a single run: Rapid and comprehensive in vitro interaction assay","volume":"24","author":"Miia","year":"2005","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s00204-008-0332-8","article-title":"Inhibition and induction of human cytochrome P450 enzymes: Current status","volume":"82","author":"Pelkonen","year":"2008","journal-title":"Arch. Toxicol."},{"key":"ref_51","unstructured":"Segel, I.H. (1975). Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady State Systems, Wiley."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_53","first-page":"57","article-title":"Python: A programming language for software integration and development","volume":"17","author":"Sanner","year":"1999","journal-title":"J. Mol. Graph. Model."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function","volume":"19","author":"Morris","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.fct.2014.01.028","article-title":"Absorption, tissue distribution, tissue metabolism and safety of \u03b1-mangostin in mangosteen extract using mouse models","volume":"66","author":"Han","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/jps.2600710432","article-title":"General derivation of the equation for time to reach a certain fraction of steady state","volume":"71","author":"Gibaldi","year":"1982","journal-title":"J. Pharm. Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/3\/555\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:57:17Z","timestamp":1760194637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/3\/555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,2]]},"references-count":56,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["molecules23030555"],"URL":"https:\/\/doi.org\/10.3390\/molecules23030555","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,2]]}}}