Modulatory Effect of Theaflavins on Apical Sodium-Dependent Bile Acid Transporter (ASBT) Activity
Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the ta...
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| Veröffentlicht in: | Journal of agricultural and food chemistry 2021-08, Vol.69 (33), p.9585-9596 |
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| container_title | Journal of agricultural and food chemistry |
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| creator | Takashima, Yuki Ishikawa, Kazuki Miyawaki, Rina Ogawa, Mana Ishii, Takeshi Misaka, Takumi Kobayashi, Shoko |
| description | Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3′-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT’s cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake. |
| doi_str_mv | 10.1021/acs.jafc.1c03483 |
| format | Article |
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Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3′-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT’s cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake.</description><identifier>ISSN: 0021-8561</identifier><identifier>EISSN: 1520-5118</identifier><identifier>DOI: 10.1021/acs.jafc.1c03483</identifier><identifier>PMID: 34346218</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Biflavonoids - pharmacology ; Bile Acids and Salts ; Bioactive Constituents, Metabolites, and Functions ; Caco-2 Cells ; Catechin - pharmacology ; Humans ; Organic Anion Transporters, Sodium-Dependent - antagonists & inhibitors ; Organic Anion Transporters, Sodium-Dependent - genetics ; Symporters - antagonists & inhibitors ; Symporters - genetics ; Taurocholic Acid - metabolism</subject><ispartof>Journal of agricultural and food chemistry, 2021-08, Vol.69 (33), p.9585-9596</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a402t-e337979f5bf492f4c77ba0ad9ed57ebb5cf6af675fda65f387f2a696739d31b53</citedby><cites>FETCH-LOGICAL-a402t-e337979f5bf492f4c77ba0ad9ed57ebb5cf6af675fda65f387f2a696739d31b53</cites><orcidid>0000-0002-9547-5767</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jafc.1c03483$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jafc.1c03483$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2764,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34346218$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takashima, Yuki</creatorcontrib><creatorcontrib>Ishikawa, Kazuki</creatorcontrib><creatorcontrib>Miyawaki, Rina</creatorcontrib><creatorcontrib>Ogawa, Mana</creatorcontrib><creatorcontrib>Ishii, Takeshi</creatorcontrib><creatorcontrib>Misaka, Takumi</creatorcontrib><creatorcontrib>Kobayashi, Shoko</creatorcontrib><title>Modulatory Effect of Theaflavins on Apical Sodium-Dependent Bile Acid Transporter (ASBT) Activity</title><title>Journal of agricultural and food chemistry</title><addtitle>J. Agric. Food Chem</addtitle><description>Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3′-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT’s cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake.</description><subject>Biflavonoids - pharmacology</subject><subject>Bile Acids and Salts</subject><subject>Bioactive Constituents, Metabolites, and Functions</subject><subject>Caco-2 Cells</subject><subject>Catechin - pharmacology</subject><subject>Humans</subject><subject>Organic Anion Transporters, Sodium-Dependent - antagonists & inhibitors</subject><subject>Organic Anion Transporters, Sodium-Dependent - genetics</subject><subject>Symporters - antagonists & inhibitors</subject><subject>Symporters - genetics</subject><subject>Taurocholic Acid - metabolism</subject><issn>0021-8561</issn><issn>1520-5118</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kDtPwzAUhS0EoqWwMyGPIJFix3GcjG0pD6mIoWWObvwQrtI42Eml_ntSWtiYrnT0nSPdD6FrSsaUxPQBZBivwcgxlYQlGTtBQ8pjEnFKs1M0JD0TZTylA3QRwpoQknFBztGAJSxJY5oNEbw51VXQOr_Dc2O0bLEzePWpwVSwtXXArsaTxkqo8NIp222iR93oWum6xVNbaTyRVuGVhzo0zrfa49vJcrq66_PWbm27u0RnBqqgr453hD6e5qvZS7R4f36dTRYRJCRuI82YyEVueGmSPDaJFKIEAirXigtdllyaFEwquFGQcsMyYWJI81SwXDFacjZCt4fdxruvToe22NggdVVBrV0XipjzjOSE8KxHyQGV3oXgtSkabzfgdwUlxV5s0Yst9mKLo9i-cnNc78qNVn-FX5M9cH8Afqqu83X_7P9733nihDo</recordid><startdate>20210825</startdate><enddate>20210825</enddate><creator>Takashima, Yuki</creator><creator>Ishikawa, Kazuki</creator><creator>Miyawaki, Rina</creator><creator>Ogawa, Mana</creator><creator>Ishii, Takeshi</creator><creator>Misaka, Takumi</creator><creator>Kobayashi, Shoko</creator><general>American Chemical Society</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>7X8</scope><orcidid>https://orcid.org/0000-0002-9547-5767</orcidid></search><sort><creationdate>20210825</creationdate><title>Modulatory Effect of Theaflavins on Apical Sodium-Dependent Bile Acid Transporter (ASBT) Activity</title><author>Takashima, Yuki ; Ishikawa, Kazuki ; Miyawaki, Rina ; Ogawa, Mana ; Ishii, Takeshi ; Misaka, Takumi ; Kobayashi, Shoko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a402t-e337979f5bf492f4c77ba0ad9ed57ebb5cf6af675fda65f387f2a696739d31b53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Biflavonoids - pharmacology</topic><topic>Bile Acids and Salts</topic><topic>Bioactive Constituents, Metabolites, and Functions</topic><topic>Caco-2 Cells</topic><topic>Catechin - pharmacology</topic><topic>Humans</topic><topic>Organic Anion Transporters, Sodium-Dependent - antagonists & inhibitors</topic><topic>Organic Anion Transporters, Sodium-Dependent - genetics</topic><topic>Symporters - antagonists & inhibitors</topic><topic>Symporters - genetics</topic><topic>Taurocholic Acid - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takashima, Yuki</creatorcontrib><creatorcontrib>Ishikawa, Kazuki</creatorcontrib><creatorcontrib>Miyawaki, Rina</creatorcontrib><creatorcontrib>Ogawa, Mana</creatorcontrib><creatorcontrib>Ishii, Takeshi</creatorcontrib><creatorcontrib>Misaka, Takumi</creatorcontrib><creatorcontrib>Kobayashi, Shoko</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of agricultural and food chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takashima, Yuki</au><au>Ishikawa, Kazuki</au><au>Miyawaki, Rina</au><au>Ogawa, Mana</au><au>Ishii, Takeshi</au><au>Misaka, Takumi</au><au>Kobayashi, Shoko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulatory Effect of Theaflavins on Apical Sodium-Dependent Bile Acid Transporter (ASBT) Activity</atitle><jtitle>Journal of agricultural and food chemistry</jtitle><addtitle>J. Agric. Food Chem</addtitle><date>2021-08-25</date><risdate>2021</risdate><volume>69</volume><issue>33</issue><spage>9585</spage><epage>9596</epage><pages>9585-9596</pages><issn>0021-8561</issn><eissn>1520-5118</eissn><abstract>Inhibiting apical sodium-dependent bile acid transporter (ASBT) has been identified as a potential strategy to reduce plasma cholesterol levels. Thus, in this study, we aimed to identify polyphenols that inhibited ASBT activity and to elucidate their mechanism. ASBT is responsible for most of the taurocholic acid (TC) uptake in Caco-2 cells. Of the 39 polyphenols examined, theaflavin (TF)-3-gallate (TF2A) and theaflavin-3′-gallate (TF2B) have been found to significantly reduce TC uptake in Caco-2 cells to 37.4 ± 2.8 and 33.8 ± 4.0%, respectively, of that in the untreated cells. The results from the TC uptake assay using N-acetylcysteine suggested that the inhibitory effect of TF2A and TF2B was attributed to the oxidization of their benzotropolone rings and their covalent bonding with ASBT’s cysteine. TC uptake was reduced in the COS-7 cells expressing recombinant ASBT whose cysteine residues were mutated to alanine. Finally, the substrate concentration-dependent TC uptake assay showed that TFs competitively inhibited TC uptake.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34346218</pmid><doi>10.1021/acs.jafc.1c03483</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-9547-5767</orcidid></addata></record> |
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| subjects | Biflavonoids - pharmacology Bile Acids and Salts Bioactive Constituents, Metabolites, and Functions Caco-2 Cells Catechin - pharmacology Humans Organic Anion Transporters, Sodium-Dependent - antagonists & inhibitors Organic Anion Transporters, Sodium-Dependent - genetics Symporters - antagonists & inhibitors Symporters - genetics Taurocholic Acid - metabolism |
| title | Modulatory Effect of Theaflavins on Apical Sodium-Dependent Bile Acid Transporter (ASBT) Activity |
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