{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T06:07:02Z","timestamp":1789020422387,"version":"build-2803163510"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    St. John\u2019s Wort (SJW;\n                    <jats:italic>Hypericum perforatum<\/jats:italic>\n                    ) is widely used for mild-to-moderate depression and is known to induce certain cytochrome P450 enzymes (notably CYP3A4, with reported effects on CYP2C9 and CYP2C19) and intestinal P-glycoprotein, but its effects on UDP-glucuronosyltransferases (UGTs), the principal phase-II drug-metabolizing enzymes, remain largely uncharacterized. Using recombinant human UGTs with 4-methylumbelliferone as the probe substrate, we characterized inhibition by the two major SJW constituents, hypericin and hyperforin, across eleven isoforms, and combined AlphaFold2-based molecular docking, molecular dynamics, and MM\/PBSA analyses with FDA 2020 static-model\n                    <jats:italic>in vitro\u2013in vivo<\/jats:italic>\n                    extrapolation (IVIVE) to predict drug\u2013drug interaction (DDI) risk. Both compounds were broad-spectrum UGT inhibitors, with hyperforin the most potent (UGT1A1\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    = 1.46 \u03bcM; UGT2B7\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    = 6.70\u00a0\u03bcM). On the clinically critical UGT1A1, hyperforin and hypericin occupied the aglycone pocket through two structurally distinct binding modes that both produced noncompetitive kinetics. Under a complete-dissolution assumption, IVIVE flagged hyperforin as a high-risk intestinal UGT inhibitor (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>1,gut<\/jats:sub>\n                    = 69.49 for UGT1A1 and 15.93 for UGT2B7, far above the FDA threshold of 11); however, incorporating hyperforin\u2019s poor (\u223c2%) dissolution and acid instability lowered the corrected\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sub>1,gut<\/jats:sub>\n                    to \u223c2.0\u20132.9 (UGT1A1) and \u223c1.2\u20131.4 (UGT2B7), indicating a potential rather than definitive intestinal interaction whose magnitude depends on the SJW formulation. These findings provide mechanistic and quantitative support for reported clinical SJW\u2013drug interactions and highlight intestinal glucuronidation as a previously underappreciated SJW-mediated DDI pathway.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1899795","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:33:11Z","timestamp":1789018391000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypericin and hyperforin from St. John\u2019s Wort are potent intestinal UGT inhibitors with distinct binding modes: mechanistic and quantitative prediction of clinical drug\u2013drug interaction risk"],"prefix":"10.3389","volume":"17","author":[{"given":"Jinqian","family":"Chen","sequence":"first","affiliation":[{"name":"NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tianjin Medical College","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xixi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Cui","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Xu","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxia","family":"Liu","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"NHC Key Lab of Hormones and Development and Tianjin Key Lab of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Institute of Endocrinology","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xichuan","family":"Li","sequence":"additional","affiliation":[{"name":"Tianjin Key Laboratory of Animal and Plant Resistance, College of Life Sciences, Tianjin Normal University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"W530","DOI":"10.1093\/nar\/gkab294","article-title":"PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA","volume":"49","author":"Adasme","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B3","doi-asserted-by":"publisher","first-page":"6156","DOI":"10.1021\/jf0490596","article-title":"Instability of st. 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