College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
Dalian Runsheng Kangtai Medical Laboratory Co., Ltd., Dalian 116000, China.
Chin J Nat Med. 2022 Jul;20(7):506-517. doi: 10.1016/S1875-5364(22)60163-8.
Gut bacterial nitroreductases play an important role in reduction of various nitroaromatic compounds to the corresponding N-nitroso compounds, hydroxylamines or aromatic amines, most of which are carcinogenic and mutagenic agents. Inhibition of gut nitroreductases has been recognized as an attractive approach for reducing mutagen metabolites in the colon, so as to prevent colon diseases. In this study, the inhibitory effects of 55 herbal medicines against Escherichia coli(E. coli) nitroreductase (EcNfsA) were examined. Compared with other herbal extracts, Syzygium aromaticum extract showed superior inhibitory potency toward EcNfsA mediated nitrofurazone reduction. Then, the inhibitory effects of 22 major constituents in Syzygium aromaticum against EcNfsA were evaluted. Compared with other tested natural compounds, ellagic acid, corilagin, betulinic acid, oleanic acid, ursolic acid, urolithin M5 and isorhamnetin were found with strong to moderate inhibitory effect against EcNfsA, with IC values ranging from 0.67 to 28.98 mol·L. Furthermore, the inhibition kinetic analysis and docking simulation demonstrated that ellagic acid and betulinic acid potently inhibited EcNfsA (K < 2 μmol·L ) in a competitively inhibitory manner, which created strong interactions with the catalytic triad of EcNfsA. In summary, our findings provide new scientific basis for explaining the anti-mutagenic activity of Syzygium aromaticum, where some newly identified EcNfsA inhibitors can be used for developing novel agents to reduce the toxicity induced by bacterial nitroreductase.
肠道细菌硝基还原酶在还原各种硝基芳香族化合物为相应的亚硝胺化合物、羟胺或芳香族胺方面发挥着重要作用，其中大多数是致癌和致突变剂。抑制肠道硝基还原酶已被认为是减少结肠中致突变代谢物的一种有吸引力的方法，从而预防结肠疾病。在这项研究中，检查了 55 种草药对大肠杆菌(E. coli)硝基还原酶（EcNfsA）的抑制作用。与其他草药提取物相比，丁香提取物对 EcNfsA 介导的硝基呋喃唑还原具有优越的抑制效力。然后，评估了丁香中 22 种主要成分对 EcNfsA 的抑制作用。与其他测试的天然化合物相比，鞣花酸、柯里拉京、齐墩果酸、熊果酸、乌索酸、尿石素 M5 和异鼠李素对 EcNfsA 具有强至中度抑制作用，IC 值范围为 0.67 至 28.98 mol·L。此外，抑制动力学分析和对接模拟表明，鞣花酸和齐墩果酸强烈抑制 EcNfsA（K < 2 μmol·L），以竞争性抑制方式，与 EcNfsA 的催化三联体形成强烈相互作用。总之，我们的发现为解释丁香的抗致突变活性提供了新的科学依据，其中一些新鉴定的 EcNfsA 抑制剂可用于开发新型药物来降低细菌硝基还原酶引起的毒性。
