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

Shinichiro Kimura, Toyoshi Inoguchi, Toshihide Yamasaki, Mayumi Yamato, Makoto Ide, Noriyuki Sonoda, Ken-Ichi Yamada, Ryoichi Takayanagi

研究成果: ジャーナルへの寄稿記事

19 引用 (Scopus)

抄録

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.

元の言語英語
ページ(範囲)138-145
ページ数8
ジャーナルMetabolism: Clinical and Experimental
65
発行部数3
DOI
出版物ステータス出版済み - 3 1 2016

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Dipeptidyl-Peptidase IV Inhibitors
Electron Spin Resonance Spectroscopy
Hydroxyl Radical
Dipeptidyl Peptidase 4
Experimental Diabetes Mellitus
rat DPP4 protein
3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine
In Vitro Techniques
Xanthine Oxidase
Diabetes Complications
Thin Layer Chromatography
Superoxides
Free Radicals
Glutathione
Aorta
Mass Spectrometry
Body Weight
Urine
Oxygen
Kidney

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

これを引用

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. / Kimura, Shinichiro; Inoguchi, Toyoshi; Yamasaki, Toshihide; Yamato, Mayumi; Ide, Makoto; Sonoda, Noriyuki; Yamada, Ken-Ichi; Takayanagi, Ryoichi.

:: Metabolism: Clinical and Experimental, 巻 65, 番号 3, 01.03.2016, p. 138-145.

研究成果: ジャーナルへの寄稿記事

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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.",
author = "Shinichiro Kimura and Toyoshi Inoguchi and Toshihide Yamasaki and Mayumi Yamato and Makoto Ide and Noriyuki Sonoda and Ken-Ichi Yamada and Ryoichi Takayanagi",
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T1 - A novel DPP-4 inhibitor teneligliptin scavenges hydroxyl radicals

T2 - In vitro study evaluated by electron spin resonance spectroscopy and in vivo study using DPP-4 deficient rats

AU - Kimura, Shinichiro

AU - Inoguchi, Toyoshi

AU - Yamasaki, Toshihide

AU - Yamato, Mayumi

AU - Ide, Makoto

AU - Sonoda, Noriyuki

AU - Yamada, Ken-Ichi

AU - Takayanagi, Ryoichi

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

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