A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats
Abstract Aims Recently various dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged because of their high effectiveness and safety. In spite of their common effect of DPP-4 inhibition, the chemical structures are diverse. Here we show that the structure of teneligliptin, a novel DPP-4 inhibitor, h...
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Veröffentlicht in: | Metabolism, clinical and experimental clinical and experimental, 2016-03, Vol.65 (3), p.138-145 |
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creator | Kimura, Shinichiro Inoguchi, Toyoshi Yamasaki, Toshihide Yamato, Mayumi Ide, Makoto Sonoda, Noriyuki Yamada, Kenichi Takayanagi, Ryoichi |
description | Abstract Aims Recently various dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged because of their high effectiveness and safety. In spite of their common effect of DPP-4 inhibition, the chemical structures are diverse. Here we show that the structure of teneligliptin, a novel DPP-4 inhibitor, has a scavenging activity on hydroxyl radical (·OH). Methods ·OH and superoxide (O2− ) were detected by electron spin resonance (ESR) spectroscopy. ·OH and O2− were generated in vitro by the Fenton reaction and a hypoxanthine-xanthine oxidase system, respectively. The level of free radicals was estimated from the ESR signal intensity. The product via teneligliptin and ·OH reaction was identified by thin layer chromatography and mass spectrometry analysis. In vivo effect was also evaluated using DPP-4 deficient rats with streptozotocin-induced diabetes. Results ESR spectroscopy analysis showed that teneligliptin did not scavenge O2− , but scavenged ·OH in a dose dependent manner. Its activity was greater than that of glutathione. The reaction product appeared to have an oxygen-atom added structure to that of teneligliptin, which was identical to the most abundant metabolite of teneligliptin in human plasma. Furthermore, using DPP-4 deficient rat, teneligliptin did not affect plasma glucose levels or body weight, but normalized increased levels of 8-hydroxy-2′-deoxyguanosine in urine, kidney and aorta of diabetic rats, supporting that teneligliptin may have a ·OH scavenging activity in vivo independently of DPP-4 inhibition. Conclusions Teneligliptin is not only effective as DPP-4 inhibitor, but may also be beneficial as ·OH scavenger, which may be useful in the prevention of diabetic complications. |
doi_str_mv | 10.1016/j.metabol.2015.10.030 |
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In spite of their common effect of DPP-4 inhibition, the chemical structures are diverse. Here we show that the structure of teneligliptin, a novel DPP-4 inhibitor, has a scavenging activity on hydroxyl radical (·OH). Methods ·OH and superoxide (O2− ) were detected by electron spin resonance (ESR) spectroscopy. ·OH and O2− were generated in vitro by the Fenton reaction and a hypoxanthine-xanthine oxidase system, respectively. The level of free radicals was estimated from the ESR signal intensity. The product via teneligliptin and ·OH reaction was identified by thin layer chromatography and mass spectrometry analysis. In vivo effect was also evaluated using DPP-4 deficient rats with streptozotocin-induced diabetes. Results ESR spectroscopy analysis showed that teneligliptin did not scavenge O2− , but scavenged ·OH in a dose dependent manner. Its activity was greater than that of glutathione. The reaction product appeared to have an oxygen-atom added structure to that of teneligliptin, which was identical to the most abundant metabolite of teneligliptin in human plasma. Furthermore, using DPP-4 deficient rat, teneligliptin did not affect plasma glucose levels or body weight, but normalized increased levels of 8-hydroxy-2′-deoxyguanosine in urine, kidney and aorta of diabetic rats, supporting that teneligliptin may have a ·OH scavenging activity in vivo independently of DPP-4 inhibition. Conclusions Teneligliptin is not only effective as DPP-4 inhibitor, but may also be beneficial as ·OH scavenger, which may be useful in the prevention of diabetic complications.</description><identifier>ISSN: 0026-0495</identifier><identifier>EISSN: 1532-8600</identifier><identifier>DOI: 10.1016/j.metabol.2015.10.030</identifier><identifier>PMID: 26892525</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Blood Glucose - metabolism ; Chromatography, Thin Layer ; Diabetes Mellitus, Experimental - metabolism ; Dipeptidyl Peptidase 4 - deficiency ; Dipeptidyl Peptidase 4 - genetics ; Dipeptidyl-Peptidase IV Inhibitors - pharmacology ; Dose-Response Relationship, Drug ; DPP-4 inhibitor ; Electron spin resonance ; Electron Spin Resonance Spectroscopy ; Endocrinology & Metabolism ; Free Radical Scavengers - pharmacology ; Hydroxyl Radical - metabolism ; Oxidative stress ; Pyrazoles - pharmacology ; Radical scavenging activity ; Rats ; Rats, Inbred F344 ; Reactive Oxygen Species - metabolism ; Teneligliptin ; Thiazolidines - pharmacology</subject><ispartof>Metabolism, clinical and experimental, 2016-03, Vol.65 (3), p.138-145</ispartof><rights>Elsevier Inc.</rights><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c584t-94235a84ba7d07efde33d206b638ba8892fc581881d32d1ebe8961233c8d9dc23</citedby><cites>FETCH-LOGICAL-c584t-94235a84ba7d07efde33d206b638ba8892fc581881d32d1ebe8961233c8d9dc23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.metabol.2015.10.030$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26892525$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kimura, Shinichiro</creatorcontrib><creatorcontrib>Inoguchi, Toyoshi</creatorcontrib><creatorcontrib>Yamasaki, Toshihide</creatorcontrib><creatorcontrib>Yamato, Mayumi</creatorcontrib><creatorcontrib>Ide, Makoto</creatorcontrib><creatorcontrib>Sonoda, Noriyuki</creatorcontrib><creatorcontrib>Yamada, Kenichi</creatorcontrib><creatorcontrib>Takayanagi, Ryoichi</creatorcontrib><title>A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats</title><title>Metabolism, clinical and experimental</title><addtitle>Metabolism</addtitle><description>Abstract Aims Recently various dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged because of their high effectiveness and safety. In spite of their common effect of DPP-4 inhibition, the chemical structures are diverse. Here we show that the structure of teneligliptin, a novel DPP-4 inhibitor, has a scavenging activity on hydroxyl radical (·OH). Methods ·OH and superoxide (O2− ) were detected by electron spin resonance (ESR) spectroscopy. ·OH and O2− were generated in vitro by the Fenton reaction and a hypoxanthine-xanthine oxidase system, respectively. The level of free radicals was estimated from the ESR signal intensity. The product via teneligliptin and ·OH reaction was identified by thin layer chromatography and mass spectrometry analysis. In vivo effect was also evaluated using DPP-4 deficient rats with streptozotocin-induced diabetes. Results ESR spectroscopy analysis showed that teneligliptin did not scavenge O2− , but scavenged ·OH in a dose dependent manner. Its activity was greater than that of glutathione. The reaction product appeared to have an oxygen-atom added structure to that of teneligliptin, which was identical to the most abundant metabolite of teneligliptin in human plasma. Furthermore, using DPP-4 deficient rat, teneligliptin did not affect plasma glucose levels or body weight, but normalized increased levels of 8-hydroxy-2′-deoxyguanosine in urine, kidney and aorta of diabetic rats, supporting that teneligliptin may have a ·OH scavenging activity in vivo independently of DPP-4 inhibition. Conclusions Teneligliptin is not only effective as DPP-4 inhibitor, but may also be beneficial as ·OH scavenger, which may be useful in the prevention of diabetic complications.</description><subject>Animals</subject><subject>Blood Glucose - metabolism</subject><subject>Chromatography, Thin Layer</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Dipeptidyl Peptidase 4 - deficiency</subject><subject>Dipeptidyl Peptidase 4 - genetics</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>DPP-4 inhibitor</subject><subject>Electron spin resonance</subject><subject>Electron Spin Resonance Spectroscopy</subject><subject>Endocrinology & Metabolism</subject><subject>Free Radical Scavengers - pharmacology</subject><subject>Hydroxyl Radical - metabolism</subject><subject>Oxidative stress</subject><subject>Pyrazoles - pharmacology</subject><subject>Radical scavenging activity</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Teneligliptin</subject><subject>Thiazolidines - pharmacology</subject><issn>0026-0495</issn><issn>1532-8600</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUstu1DAUjRCIDoVPAHnJJoMfeTgsQFXLo1IlKgFry7Fvph48drCdiPwVn4jDTFmw6cq618fn-J5zi-IlwVuCSfNmvz1Akr23W4pJnXtbzPCjYkNqRkveYPy42GBMmxJXXX1WPItxjzFuW948Lc5owzta03pT_L5Azs9g0dXtbVkh4-5Mb5IPKIEDa3bWjMk4FJWcwe0gortFB_9rsShIbZS08S26dmg2KXgU06QXBLO0k0ygUZ8LCypfZYYx0wSI3kmnIJd_-1H5cUHS6aycSeZ7jikatzv9ScNglAGXsmSKz4snQ1aFF6fzvPj-8cO3y8_lzZdP15cXN6WqeZXKrqKslrzqZatxC4MGxjTFTd8w3kuexx8ykHBONKOaQA-8awhlTHHdaUXZefH6yDsG_3OCmMTBRAXWSgd-ioJwQrrsZ1s9DG2bFrdVxesMrY9QlWePAQYxBnOQYREEizVXsRenXMWa69rOueZ3r04SU38A_e_VfZAZ8P4IgOzJbCCIuHqmQJuQnRbamwcl3v3HoKxxa8Q_YIG491Nw2XBBRKQCi6_rcq27RWqMGWsq9gcWJs5E</recordid><startdate>20160301</startdate><enddate>20160301</enddate><creator>Kimura, Shinichiro</creator><creator>Inoguchi, Toyoshi</creator><creator>Yamasaki, Toshihide</creator><creator>Yamato, Mayumi</creator><creator>Ide, Makoto</creator><creator>Sonoda, Noriyuki</creator><creator>Yamada, Kenichi</creator><creator>Takayanagi, Ryoichi</creator><general>Elsevier Inc</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><scope>7TS</scope></search><sort><creationdate>20160301</creationdate><title>A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats</title><author>Kimura, Shinichiro ; Inoguchi, Toyoshi ; Yamasaki, Toshihide ; Yamato, Mayumi ; Ide, Makoto ; Sonoda, Noriyuki ; Yamada, Kenichi ; Takayanagi, Ryoichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c584t-94235a84ba7d07efde33d206b638ba8892fc581881d32d1ebe8961233c8d9dc23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Blood Glucose - metabolism</topic><topic>Chromatography, Thin Layer</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Dipeptidyl Peptidase 4 - deficiency</topic><topic>Dipeptidyl Peptidase 4 - genetics</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>DPP-4 inhibitor</topic><topic>Electron spin resonance</topic><topic>Electron Spin Resonance Spectroscopy</topic><topic>Endocrinology & Metabolism</topic><topic>Free Radical Scavengers - pharmacology</topic><topic>Hydroxyl Radical - metabolism</topic><topic>Oxidative stress</topic><topic>Pyrazoles - pharmacology</topic><topic>Radical scavenging activity</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Teneligliptin</topic><topic>Thiazolidines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kimura, Shinichiro</creatorcontrib><creatorcontrib>Inoguchi, Toyoshi</creatorcontrib><creatorcontrib>Yamasaki, Toshihide</creatorcontrib><creatorcontrib>Yamato, Mayumi</creatorcontrib><creatorcontrib>Ide, Makoto</creatorcontrib><creatorcontrib>Sonoda, Noriyuki</creatorcontrib><creatorcontrib>Yamada, Kenichi</creatorcontrib><creatorcontrib>Takayanagi, Ryoichi</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><collection>Physical Education Index</collection><jtitle>Metabolism, clinical and experimental</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kimura, Shinichiro</au><au>Inoguchi, Toyoshi</au><au>Yamasaki, Toshihide</au><au>Yamato, Mayumi</au><au>Ide, Makoto</au><au>Sonoda, Noriyuki</au><au>Yamada, Kenichi</au><au>Takayanagi, Ryoichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats</atitle><jtitle>Metabolism, clinical and experimental</jtitle><addtitle>Metabolism</addtitle><date>2016-03-01</date><risdate>2016</risdate><volume>65</volume><issue>3</issue><spage>138</spage><epage>145</epage><pages>138-145</pages><issn>0026-0495</issn><eissn>1532-8600</eissn><abstract>Abstract Aims Recently various dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged because of their high effectiveness and safety. In spite of their common effect of DPP-4 inhibition, the chemical structures are diverse. Here we show that the structure of teneligliptin, a novel DPP-4 inhibitor, has a scavenging activity on hydroxyl radical (·OH). Methods ·OH and superoxide (O2− ) were detected by electron spin resonance (ESR) spectroscopy. ·OH and O2− were generated in vitro by the Fenton reaction and a hypoxanthine-xanthine oxidase system, respectively. The level of free radicals was estimated from the ESR signal intensity. The product via teneligliptin and ·OH reaction was identified by thin layer chromatography and mass spectrometry analysis. In vivo effect was also evaluated using DPP-4 deficient rats with streptozotocin-induced diabetes. Results ESR spectroscopy analysis showed that teneligliptin did not scavenge O2− , but scavenged ·OH in a dose dependent manner. Its activity was greater than that of glutathione. The reaction product appeared to have an oxygen-atom added structure to that of teneligliptin, which was identical to the most abundant metabolite of teneligliptin in human plasma. Furthermore, using DPP-4 deficient rat, teneligliptin did not affect plasma glucose levels or body weight, but normalized increased levels of 8-hydroxy-2′-deoxyguanosine in urine, kidney and aorta of diabetic rats, supporting that teneligliptin may have a ·OH scavenging activity in vivo independently of DPP-4 inhibition. Conclusions Teneligliptin is not only effective as DPP-4 inhibitor, but may also be beneficial as ·OH scavenger, which may be useful in the prevention of diabetic complications.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26892525</pmid><doi>10.1016/j.metabol.2015.10.030</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Blood Glucose - metabolism Chromatography, Thin Layer Diabetes Mellitus, Experimental - metabolism Dipeptidyl Peptidase 4 - deficiency Dipeptidyl Peptidase 4 - genetics Dipeptidyl-Peptidase IV Inhibitors - pharmacology Dose-Response Relationship, Drug DPP-4 inhibitor Electron spin resonance Electron Spin Resonance Spectroscopy Endocrinology & Metabolism Free Radical Scavengers - pharmacology Hydroxyl Radical - metabolism Oxidative stress Pyrazoles - pharmacology Radical scavenging activity Rats Rats, Inbred F344 Reactive Oxygen Species - metabolism Teneligliptin Thiazolidines - pharmacology |
title | A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals: In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats |
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