Kimura Shinichiro, Inoguchi Toyoshi, Yamasaki Toshihide, Yamato Mayumi, Ide Makoto, Sonoda Noriyuki, Yamada Kenichi, Takayanagi Ryoichi
The Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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.
Metabolism. 2016 Mar;65(3):138-45. doi: 10.1016/j.metabol.2015.10.030. Epub 2015 Nov 2.
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).
·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.
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.
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.
近来，各种二肽基肽酶-4（DPP-4）抑制剂因其高效性和安全性而出现。尽管它们具有共同的DPP-4抑制作用，但其化学结构各不相同。在此，我们表明新型DPP-4抑制剂替格列汀的结构对羟自由基（·OH）具有清除活性。
通过电子自旋共振（ESR）光谱检测·OH和超氧阴离子（O2(-)）。·OH和O2(-)分别通过芬顿反应和次黄嘌呤-黄嘌呤氧化酶系统在体外产生。自由基水平根据ESR信号强度进行估计。通过薄层色谱和质谱分析鉴定替格列汀与·OH反应的产物。还使用链脲佐菌素诱导糖尿病的DPP-4缺陷大鼠评估体内效应。
ESR光谱分析表明，替格列汀不清除O2(-)，但以剂量依赖方式清除·OH。其活性大于谷胱甘肽。反应产物似乎在替格列汀结构上添加了一个氧原子，这与替格列汀在人血浆中最丰富的代谢物相同。此外，使用DPP-4缺陷大鼠，替格列汀不影响血糖水平或体重，但使糖尿病大鼠尿液、肾脏和主动脉中升高的8-羟基-2'-脱氧鸟苷水平恢复正常，支持替格列汀可能在体内具有独立于DPP-4抑制的·OH清除活性。
替格列汀不仅作为DPP-4抑制剂有效，而且作为·OH清除剂可能也有益，这可能对预防糖尿病并发症有用。
