Shinichiro Kimura1, Toyoshi Inoguchi2, Toshihide Yamasaki3, Mayumi Yamato4, Makoto Ide1, Noriyuki Sonoda5, Kenichi Yamada3, Ryoichi Takayanagi1. 1. The Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 2. The Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; The Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. Electronic address: toyoshi@intmed3.med.kyushu-u.ac.jp. 3. The Department of Bio-functional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. 4. The Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan. 5. The Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; The Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan.
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.
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 diabeticrats, 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.