Mechanism of the efflux transport of demethoxycurcumin-O-glucuronides in HeLa cells stably transfected with UDP-glucuronosyltransferase 1A1
Demethoxycurcumin (DMC) is a safe and natural food-coloring additive, as well as an agent with several therapeutic properties. However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5&...
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| Veröffentlicht in: | PloS one 2019-05, Vol.14 (5), p.e0217695-e0217695 |
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| creator | Zhang, Beibei Yang, Jing Qin, Zifei Li, Shishi Xu, Jinjin Yao, Zhihong Zhang, Xiaojian Gonzalez, Frank J Yao, Xinsheng |
| description | Demethoxycurcumin (DMC) is a safe and natural food-coloring additive, as well as an agent with several therapeutic properties. However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1 (named HeLa1A1 cells). The chemical inhibitors Ko143 (a selective BCRP inhibitor) and MK571 (a pan-MRP inhibitor) both induced an obvious decrease in the excretion rate of DMC-O-glucuronides and a significant increase in intracellular DMC-O-glucuronide concentrations. Furthermore, BCRP knock-down resulted in a marked reduction in the level of excreted DMC-O-glucuronides (maximal 55.6%), whereas MRP1 and MRP4 silencing significantly decreased the levels of excreted DMC-O-glucuronides (a maximum of 42.9% for MRP1 and a maximum of 29.9% for MRP3), respectively. In contrast, neither the levels of excreted DMC-O-glucuronides nor the accumulation of DMC-O-glucuronides were significantly altered in the MRP4 knock-down HeLa cells. The BCRP, MRP1 and MRP3 transporters were identified as the most important contributors to the excretion of DMC-O-glucuronides. These results may significantly contribute to improving our understanding of mechanisms underlying the cellular disposition of DMC via UGT-mediated metabolism. |
| doi_str_mv | 10.1371/journal.pone.0217695 |
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However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1 (named HeLa1A1 cells). The chemical inhibitors Ko143 (a selective BCRP inhibitor) and MK571 (a pan-MRP inhibitor) both induced an obvious decrease in the excretion rate of DMC-O-glucuronides and a significant increase in intracellular DMC-O-glucuronide concentrations. Furthermore, BCRP knock-down resulted in a marked reduction in the level of excreted DMC-O-glucuronides (maximal 55.6%), whereas MRP1 and MRP4 silencing significantly decreased the levels of excreted DMC-O-glucuronides (a maximum of 42.9% for MRP1 and a maximum of 29.9% for MRP3), respectively. In contrast, neither the levels of excreted DMC-O-glucuronides nor the accumulation of DMC-O-glucuronides were significantly altered in the MRP4 knock-down HeLa cells. The BCRP, MRP1 and MRP3 transporters were identified as the most important contributors to the excretion of DMC-O-glucuronides. These results may significantly contribute to improving our understanding of mechanisms underlying the cellular disposition of DMC via UGT-mediated metabolism.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0217695</identifier><identifier>PMID: 31150474</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alzheimer's disease ; ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics ; Bioavailability ; Biological Availability ; Biology and Life Sciences ; Blood-brain barrier ; Brain research ; Breast cancer ; Cancer therapies ; Chemical compounds ; Coloring ; Diarylheptanoids - chemistry ; Diarylheptanoids - pharmacology ; Diketopiperazines - pharmacology ; Drugs ; Efflux ; Excretion ; Food additives ; Food Coloring Agents - chemistry ; Food Coloring Agents - pharmacology ; Food dyes ; Gene Silencing ; Glucuronides - biosynthesis ; Glucuronides - genetics ; Glucuronosyltransferase ; Glucuronosyltransferase - chemistry ; Glucuronosyltransferase - genetics ; HeLa Cells ; Heterocyclic Compounds, 4 or More Rings - pharmacology ; Humans ; In vivo methods and tests ; Inhibitors ; Laboratories ; Levels ; Material requirements planning ; Medical research ; Medicine and Health Sciences ; Metabolism ; Metabolites ; MRP protein ; Multidrug resistance ; Multidrug Resistance-Associated Proteins - antagonists & inhibitors ; Multidrug Resistance-Associated Proteins - genetics ; Natural & organic foods ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - genetics ; NMR ; Nuclear magnetic resonance ; Organic chemistry ; Pharmacology ; Pharmacy ; Phytochemicals ; Propionates - pharmacology ; Protein Transport - genetics ; Proteins ; Quinolines - pharmacology ; Research and analysis methods ; Transfection ; Transport ; UDP-glucuronosyltransferase ; Uridine</subject><ispartof>PloS one, 2019-05, Vol.14 (5), p.e0217695-e0217695</ispartof><rights>2019 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Zhang et al 2019 Zhang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-3540fcfd858c6d9e6935cea2906e0acc01466dbeedd45c16e8641b01e25da5963</citedby><cites>FETCH-LOGICAL-c526t-3540fcfd858c6d9e6935cea2906e0acc01466dbeedd45c16e8641b01e25da5963</cites><orcidid>0000-0001-8989-1986</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544300/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544300/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31150474$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Hsieh, Yi-Hsien</contributor><creatorcontrib>Zhang, Beibei</creatorcontrib><creatorcontrib>Yang, Jing</creatorcontrib><creatorcontrib>Qin, Zifei</creatorcontrib><creatorcontrib>Li, Shishi</creatorcontrib><creatorcontrib>Xu, Jinjin</creatorcontrib><creatorcontrib>Yao, Zhihong</creatorcontrib><creatorcontrib>Zhang, Xiaojian</creatorcontrib><creatorcontrib>Gonzalez, Frank J</creatorcontrib><creatorcontrib>Yao, Xinsheng</creatorcontrib><title>Mechanism of the efflux transport of demethoxycurcumin-O-glucuronides in HeLa cells stably transfected with UDP-glucuronosyltransferase 1A1</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Demethoxycurcumin (DMC) is a safe and natural food-coloring additive, as well as an agent with several therapeutic properties. However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1 (named HeLa1A1 cells). The chemical inhibitors Ko143 (a selective BCRP inhibitor) and MK571 (a pan-MRP inhibitor) both induced an obvious decrease in the excretion rate of DMC-O-glucuronides and a significant increase in intracellular DMC-O-glucuronide concentrations. Furthermore, BCRP knock-down resulted in a marked reduction in the level of excreted DMC-O-glucuronides (maximal 55.6%), whereas MRP1 and MRP4 silencing significantly decreased the levels of excreted DMC-O-glucuronides (a maximum of 42.9% for MRP1 and a maximum of 29.9% for MRP3), respectively. In contrast, neither the levels of excreted DMC-O-glucuronides nor the accumulation of DMC-O-glucuronides were significantly altered in the MRP4 knock-down HeLa cells. The BCRP, MRP1 and MRP3 transporters were identified as the most important contributors to the excretion of DMC-O-glucuronides. These results may significantly contribute to improving our understanding of mechanisms underlying the cellular disposition of DMC via UGT-mediated metabolism.</description><subject>Alzheimer's disease</subject><subject>ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors</subject><subject>ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics</subject><subject>Bioavailability</subject><subject>Biological Availability</subject><subject>Biology and Life Sciences</subject><subject>Blood-brain barrier</subject><subject>Brain research</subject><subject>Breast cancer</subject><subject>Cancer therapies</subject><subject>Chemical compounds</subject><subject>Coloring</subject><subject>Diarylheptanoids - chemistry</subject><subject>Diarylheptanoids - pharmacology</subject><subject>Diketopiperazines - pharmacology</subject><subject>Drugs</subject><subject>Efflux</subject><subject>Excretion</subject><subject>Food additives</subject><subject>Food Coloring Agents - chemistry</subject><subject>Food Coloring Agents - pharmacology</subject><subject>Food dyes</subject><subject>Gene Silencing</subject><subject>Glucuronides - biosynthesis</subject><subject>Glucuronides - genetics</subject><subject>Glucuronosyltransferase</subject><subject>Glucuronosyltransferase - chemistry</subject><subject>Glucuronosyltransferase - genetics</subject><subject>HeLa Cells</subject><subject>Heterocyclic Compounds, 4 or More Rings - pharmacology</subject><subject>Humans</subject><subject>In vivo methods and tests</subject><subject>Inhibitors</subject><subject>Laboratories</subject><subject>Levels</subject><subject>Material requirements planning</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>MRP protein</subject><subject>Multidrug resistance</subject><subject>Multidrug Resistance-Associated Proteins - antagonists & inhibitors</subject><subject>Multidrug Resistance-Associated Proteins - genetics</subject><subject>Natural & organic foods</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - genetics</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Organic chemistry</subject><subject>Pharmacology</subject><subject>Pharmacy</subject><subject>Phytochemicals</subject><subject>Propionates - pharmacology</subject><subject>Protein Transport - genetics</subject><subject>Proteins</subject><subject>Quinolines - pharmacology</subject><subject>Research and analysis methods</subject><subject>Transfection</subject><subject>Transport</subject><subject>UDP-glucuronosyltransferase</subject><subject>Uridine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUstu1DAUjRCIlsIfILDEhk0Gv5NskKryaKVBZUHXlse-nmTkxIPtlM438NNkmHTUIla2r885956rUxSvCV4QVpEPmzDGQfvFNgywwJRUshFPilPSMFpKitnTB_eT4kVKG4wFq6V8XpwwQgTmFT8tfn8D0-qhSz0KDuUWEDjnxzuUox7SNsS8r1voIbfhbmfGaMa-G8rrcu3H6RWGzkJC3YAuYamRAe8TSlmv_O4g4cBksOhXl1t08-n7kRbSzs-AqBMgck5eFs-c9glezedZcfPl84-Ly3J5_fXq4nxZGkFlLpng2Blna1EbaRuQDRMGNG2wBKyNwYRLaVcA1nJhiIRacrLCBKiwWjSSnRVvD7pbH5Ka95gUpYxR0VScT4irA8IGvVHb2PU67lTQnfpbCHGtdMyd8aDqhk8b1rjSgnGuXaMpk8QJap1sHNOT1se527jqwRoYJtv-kejjn6Fr1TrcKimmSTCeBN7PAjH8HCFl1Xdpv2g9QBgPc9dC4IpO0Hf_QP_vjh9QJoaUIrjjMASrfbbuWWqfLTVna6K9eWjkSLoPE_sD0IHP-A</recordid><startdate>20190531</startdate><enddate>20190531</enddate><creator>Zhang, Beibei</creator><creator>Yang, Jing</creator><creator>Qin, Zifei</creator><creator>Li, Shishi</creator><creator>Xu, Jinjin</creator><creator>Yao, Zhihong</creator><creator>Zhang, Xiaojian</creator><creator>Gonzalez, Frank J</creator><creator>Yao, Xinsheng</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-8989-1986</orcidid></search><sort><creationdate>20190531</creationdate><title>Mechanism of the efflux transport of demethoxycurcumin-O-glucuronides in HeLa cells stably transfected with UDP-glucuronosyltransferase 1A1</title><author>Zhang, Beibei ; Yang, Jing ; Qin, Zifei ; Li, Shishi ; Xu, Jinjin ; Yao, Zhihong ; Zhang, Xiaojian ; Gonzalez, Frank J ; Yao, Xinsheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-3540fcfd858c6d9e6935cea2906e0acc01466dbeedd45c16e8641b01e25da5963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Alzheimer's disease</topic><topic>ATP Binding Cassette Transporter, Subfamily G, Member 2 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Beibei</au><au>Yang, Jing</au><au>Qin, Zifei</au><au>Li, Shishi</au><au>Xu, Jinjin</au><au>Yao, Zhihong</au><au>Zhang, Xiaojian</au><au>Gonzalez, Frank J</au><au>Yao, Xinsheng</au><au>Hsieh, Yi-Hsien</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of the efflux transport of demethoxycurcumin-O-glucuronides in HeLa cells stably transfected with UDP-glucuronosyltransferase 1A1</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-05-31</date><risdate>2019</risdate><volume>14</volume><issue>5</issue><spage>e0217695</spage><epage>e0217695</epage><pages>e0217695-e0217695</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Demethoxycurcumin (DMC) is a safe and natural food-coloring additive, as well as an agent with several therapeutic properties. However, extensive glucuronidation in vivo has resulted in its poor bioavailability. In this study, we aimed to investigate the formation of DMC-O-glucuronides by uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) and its transport by breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in HeLa cells stably transfected with UGT1A1 (named HeLa1A1 cells). The chemical inhibitors Ko143 (a selective BCRP inhibitor) and MK571 (a pan-MRP inhibitor) both induced an obvious decrease in the excretion rate of DMC-O-glucuronides and a significant increase in intracellular DMC-O-glucuronide concentrations. Furthermore, BCRP knock-down resulted in a marked reduction in the level of excreted DMC-O-glucuronides (maximal 55.6%), whereas MRP1 and MRP4 silencing significantly decreased the levels of excreted DMC-O-glucuronides (a maximum of 42.9% for MRP1 and a maximum of 29.9% for MRP3), respectively. In contrast, neither the levels of excreted DMC-O-glucuronides nor the accumulation of DMC-O-glucuronides were significantly altered in the MRP4 knock-down HeLa cells. The BCRP, MRP1 and MRP3 transporters were identified as the most important contributors to the excretion of DMC-O-glucuronides. These results may significantly contribute to improving our understanding of mechanisms underlying the cellular disposition of DMC via UGT-mediated metabolism.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31150474</pmid><doi>10.1371/journal.pone.0217695</doi><orcidid>https://orcid.org/0000-0001-8989-1986</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-05, Vol.14 (5), p.e0217695-e0217695 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2233259744 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alzheimer's disease ATP Binding Cassette Transporter, Subfamily G, Member 2 - antagonists & inhibitors ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics Bioavailability Biological Availability Biology and Life Sciences Blood-brain barrier Brain research Breast cancer Cancer therapies Chemical compounds Coloring Diarylheptanoids - chemistry Diarylheptanoids - pharmacology Diketopiperazines - pharmacology Drugs Efflux Excretion Food additives Food Coloring Agents - chemistry Food Coloring Agents - pharmacology Food dyes Gene Silencing Glucuronides - biosynthesis Glucuronides - genetics Glucuronosyltransferase Glucuronosyltransferase - chemistry Glucuronosyltransferase - genetics HeLa Cells Heterocyclic Compounds, 4 or More Rings - pharmacology Humans In vivo methods and tests Inhibitors Laboratories Levels Material requirements planning Medical research Medicine and Health Sciences Metabolism Metabolites MRP protein Multidrug resistance Multidrug Resistance-Associated Proteins - antagonists & inhibitors Multidrug Resistance-Associated Proteins - genetics Natural & organic foods Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - genetics NMR Nuclear magnetic resonance Organic chemistry Pharmacology Pharmacy Phytochemicals Propionates - pharmacology Protein Transport - genetics Proteins Quinolines - pharmacology Research and analysis methods Transfection Transport UDP-glucuronosyltransferase Uridine |
| title | Mechanism of the efflux transport of demethoxycurcumin-O-glucuronides in HeLa cells stably transfected with UDP-glucuronosyltransferase 1A1 |
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