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, Kenichi Yamada, Ryoichi Takayanagi

研究成果: ジャーナルへの寄稿学術誌査読

30 被引用数 (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.

本文言語英語
ページ(範囲)138-145
ページ数8
ジャーナルMetabolism: Clinical and Experimental
65
3
DOI
出版ステータス出版済み - 3月 1 2016

!!!All Science Journal Classification (ASJC) codes

  • 内分泌学、糖尿病および代謝内科学
  • 内分泌学

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