[{"id":24,"uid":"NPDI-OeAReg","name":"Identification of Intestinal UDP-Glucuronosyltransferase Inhibitors in Green Tea (Camellia sinensis) Using a Biochemometric Approach: Application to Raloxifene as a Test Drug via In Vitro to In Vivo Extrapolation","napdiIdentifier":"DPS-WSU-001","overallSummary":"Green tea is a commonly consumed beverage worldwide; thus, identifying green tea-drug interactions would be of high impact. The potential for UDP-glucuronosyltransferase (UGT)-based interactions are relatively understudied, particularly those in the intestine. As with all botanical dietary supplements, green tea is a complex and variable mixture of diverse phytoconstituents. Comprehensive, high-throughput, robust methods are needed to identify candidate precipitants of interactions with drugs. Using a biochemometrics approach that combines chemometrics with established bioassays, intestinal UGT inhibitors in green tea were identified and evaluated for their in vivo interaction potential. Four widely available green teas that were chemically similar to the National Institute of Standards and Technology (NIST) leaf reference material were selected for evaluation as inhibitors of intestinal UGT activity using human intestinal microsomes. Extracts and five fractions (prepared from the original extracts) of each tea were tested (20, 60, 180 µg/mL) using the nonspecific fluorescent substrate 4-methylumbelliferone. Fractions rich in UGT inhibitory constituents were identified via mass spectrometry-based untargeted metabolomics; these fractions were fractionated further and subjected to biochemometric analysis to identify individual UGT inhibitors. The K<sub>i</sub> of two of these constituents and the original extract of a representative tea were determined using raloxifene a clinically relevant substrate. The K<sub>i</sub> values were applied to a mechanistic static model to evaluate the potential for a green tea-raloxifene interaction in vivo. Effects of the extracts and fractions from all four teas were qualitatively similar, inhibiting intestinal UGT activity in a concentration-dependent manner (by 0 to &gt;95% relative to vehicle control). The UGT inhibitory constituents tended to reside in the more hydrophilic subfractions of the fraction prepared from the representative extract. (−)-Epigallocatechin gallate (EGCG) and (−)-epicatechin gallate (ECG), two abundant catechins contained in green tea, were identified as major UGT inhibitors in these subfractions. K<sub>i</sub> values were 2.0 and 0.8-1.0 μM, respectively, which were ~100x lower than concentrations measured in a 240-mL cup of hot tea prepared from the NIST leaf reference material. A biochemometric approach, which combines bioactivity data with chemometric analysis, was successfully applied to green tea for identifying intestinal UGT inhibitors that could precipitate an interaction with raloxifene and other UGT substrates (e.g., raltegravir, ezetimibe, and mycophenolic acid). This comprehensive approach could be applied to other natural products with drug interaction potential.","pubmedId":29467215,"embaseId":null,"croIdentifier":"DPS-WSU","croInformation":"Department of Pharmaceutical Sciences, Washington State University; Department of Chemistry & Biochemistry, University of North Carolina at Greensboro; Department of Population Sciences, City of Hope","dateStart":"2016-06-01T00:00:00.000Z","dateEnd":"2017-09-30T00:00:00.000Z","internalComment":"This <em>in vitro</em> study was entered from unpublised data from Dr. Mary Paine's lab. Data was curated by JS and reviewed by JY.","status":"published","compoundId":null,"naturalProductUid":"NP-028bf4b2-0bc6-458f-b86f-6930ce40efc6","naturalProductSampleId":"NPS-G8hk_A","studySourceTypeId":2,"naturalProduct":{"uid":"NP-028bf4b2-0bc6-458f-b86f-6930ce40efc6","binomial":"Camellia sinensis","name":"Green tea","itis":null,"srs":"e9698137-24da-46f8-a70e-43e27691491f","source_id":"","conceptId":null},"compound":null,"studySourceType":{"id":2,"name":"Manuscript prepared or submitted for peer-reviewed publication"},"experiments":[{"id":40,"uid":"NPDI-EczRtA","name":"Inhibition of UGT by (-)-Epigallocatechin Gallate (Screening)","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition vs. control","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Purified green tea catechins were tested as inhibitors of UGT enzymes as described in Gufford et al., 2014 (Drug Metab Dispos. 2014 Oct;42(10):1675-83); information regarding incubation volume, time, and protien linearity were obtain therein.<br />Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":"Percent inhibition was estimated from Fig. S1.","internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":37,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":42,"controlDataForExperimentId":42,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":37,"name":"(-)-epigallocatechin gallate","unii":null,"inChIKey":null,"publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":19},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":40}}],"transporters":[],"quantifiedMetabolites":[]},{"id":41,"uid":"NPDI-CWM_sQ","name":"Inhibition of UGT by (-)-Epicatechin Gallate (Screening)","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition vs. control","croIdentifier":null,"comment":"The precipitant used was (-)-epicatechin gallate.","experimentalConditionsComment":"Purified green tea catechins were tested as inhibitors of UGT enzymes as described in Gufford et al., 2014 (Drug Metab Dispos. 2014 Oct;42(10):1675-83); information regarding incubation volume, time, and protein linearity were obtain therein.<br />Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":"Percent inhibition was estimated from Fig. S1.","internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":17,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":42,"controlDataForExperimentId":42,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":17,"name":"epicatechin gallate","unii":"92587OVD8Z","inChIKey":"LSHVYAFMTMFKBA-TZIWHRDSSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":41}}],"transporters":[],"quantifiedMetabolites":[]},{"id":42,"uid":"NPDI-N39uaQ","name":"Inhibition of UGT by Nicardipine in HIM (Screening)","overallEffect":1,"isControlData":true,"isIc50Shift":false,"croCutoff":"50% inhibition vs. control","croIdentifier":null,"comment":"Nicardipine was used as the positive control inhibitor.","experimentalConditionsComment":"Purified green tea catechins were tested as inhibitors of UGT enzymes as described in Gufford et al., 2014 (Drug Metab Dispos. 2014 Oct;42(10):1675-83); information regarding incubation volume, time, and protien linearity were obtain therein.<br />Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":"Percent inhibition was estimated from Fig. S1.","internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":74,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":9,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":74,"name":"nicardipine","unii":null,"inChIKey":"ZBBHBTPTTSWHBA-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":1318137,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":42}}],"transporters":[],"quantifiedMetabolites":[]},{"id":43,"uid":"NPDI-cTDX2A","name":"Inhibition of UGT by (-)-Epicatechin (Screening)","overallEffect":0,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition vs. control","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Purified green tea catechins were tested as inhibitors of UGT enzymes as described in Gufford et al., 2014 (Drug Metab Dispos. 2014 Oct;42(10):1675-83); information regarding incubation volume, time, and protien linearity were obtain therein.<br />Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":"(-)-Epicatechin did not significantly inhibit UGT enzymes--observed UGT activity was 110% of control.","internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":66,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":42,"controlDataForExperimentId":42,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":66,"name":"(-)-epicatechin","unii":null,"inChIKey":null,"publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":16},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":43}}],"transporters":[],"quantifiedMetabolites":[]},{"id":44,"uid":"NPDI-7pd4sA","name":"Inhibition of UGT by (-)-Epigallocatechin (Screening)","overallEffect":0,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition vs. control","croIdentifier":null,"comment":"The precipitant used was (-)-epigallocatechin.","experimentalConditionsComment":"Purified green tea catechins were tested as inhibitors of UGT enzymes as described in Gufford et al., 2014 (Drug Metab Dispos. 2014 Oct;42(10):1675-83); information regarding incubation volume, time, and protien linearity were obtain therein.<br />Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":"(-)-Epigallocatechin did not significantly inhibit UGT enzymes--observed UGT activity was 110% of control.","internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":18,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":42,"controlDataForExperimentId":42,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":18,"name":"epigallocatechin","unii":"7Z197MG6QL","inChIKey":"XMOCLSLCDHWDHP-IUODEOHRSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":44}}],"transporters":[],"quantifiedMetabolites":[]},{"id":45,"uid":"NPDI-p3x0vg","name":"Inhibition of UGT by (-)-Gallocatechin (Screening)","overallEffect":0,"isControlData":false,"isIc50Shift":false,"croCutoff":"50% inhibition vs. control","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Purified green tea catechins were tested as inhibitors of UGT enzymes as described in Gufford et al., 2014 (Drug Metab Dispos. 2014 Oct;42(10):1675-83); information regarding incubation volume, time, and protien linearity were obtain therein.<br />Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":"(-)-Gallocatechin did not significantly inhibit UGT enzymes--observed UGT activity was 105% of control.","internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":36,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":42,"controlDataForExperimentId":42,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":36,"name":"(-)-gallocatechin","unii":null,"inChIKey":"XMOCLSLCDHWDHP-DOMZBBRYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":22},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":45}}],"transporters":[],"quantifiedMetabolites":[]},{"id":46,"uid":"NPDI-7el55g","name":"Inhibition of UGT by (-)-Epigallocatechin Gallate (IC50 Determination)","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"Not provided","croIdentifier":null,"comment":null,"experimentalConditionsComment":"Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":null,"internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":37,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":9,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":37,"name":"(-)-epigallocatechin gallate","unii":null,"inChIKey":null,"publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":19},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":46}}],"transporters":[],"quantifiedMetabolites":[]},{"id":47,"uid":"NPDI-AXdpJA","name":"Inhibition of UGT by (-)-Epicatechin Gallate (IC50 determination)","overallEffect":1,"isControlData":false,"isIc50Shift":false,"croCutoff":"Not provided","croIdentifier":null,"comment":"The precipitant used was (-)-epicatechin gallate.","experimentalConditionsComment":"Bovine serum albumin (0.05%) was added into the incubation system.","resultsComment":null,"internalComment":null,"objectCompoundId":70,"objectMetaboliteCompoundId":73,"precipitantCompoundId":17,"cytochromeB5Id":null,"studyId":24,"experimentTypeId":1,"testSystemId":8,"ic50ShiftExperimentId":null,"controlDataExperimentId":null,"controlDataForExperimentId":null,"naturalProductSampleId":null,"experimentType":{"id":1,"name":"In Vitro Enzyme Inhibition","isInVitro":true,"isTransporter":false,"isEnzyme":true,"purl":"http://purl.obolibrary.org/obo/DIDEO_00000058"},"objectCompound":{"id":70,"name":"4-methylumbelliferone","unii":null,"inChIKey":"HSHNITRMYYLLCV-UHFFFAOYSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"precipitantCompound":{"id":17,"name":"epicatechin gallate","unii":"92587OVD8Z","inChIKey":"LSHVYAFMTMFKBA-TZIWHRDSSA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"objectMetaboliteCompound":{"id":73,"name":"4-methylumbelliferone glucuronide","unii":null,"inChIKey":"ARQXEQLMMNGFDU-JHZZJYKESA-N","publicDescription":null,"internalComment":null,"conceptId":null,"enantiomerOfId":null},"enzymes":[{"id":27,"name":"UGT","conceptId":null,"experiment_enzyme_xref":{"enzymeId":27,"experimentId":47}}],"transporters":[],"quantifiedMetabolites":[]},{"id":48,"uid":"NPDI--hYNlQ","name":"Inhibition of UGT1A1, 1A8, and 1A10 by Nicardipine (Positive Control; 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