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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• 作者：Shinichiro Kimura^a ; Toyoshi Inoguchi^a ; ^b ; ^{toyoshi@intmed3.med.kyushu-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Toshihide Yamasaki^c ; Mayumi Yamato^b ; Makoto Ide^a ; Noriyuki Sonoda^a ; ^b ; Kenichi Yamada^c ; Ryoichi Takayanagi^a
• 关键词：DPP-4 ; dipeptidyl peptidase-4 ; GLP-1 ; glucagon-like peptide-1 ; · ; OH ; hydroxyl-radical ; O2&minus ; superoxide ; ESR ; electron spin resonance ; 8-OHdG ; 8-hydroxy-2&prime ; -deoxyguanosine ; XOD ; xanthine oxidase ; DMPO ; 5.5-dimethyl-l-pyrroline-N-oxide ; HPX ; hypoxanthine ; TLC ; thin-layer chromatography ; HRMS ; high-resolution mass spectrometry ; F344 ; Fischer 344 ; STZ ; streptozotocin ; ELISA ; enzyme-linked immunosorbent assay ; IC50 ; half maximal inhibitory concentration ; ROS ; reactive oxygen species
• 刊名：Metabolism
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：65
• 期：3
• 页码：138-145
• 全文大小：1601 K

文摘

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.