Skullcapflavone II是一种新型的NQO1抑制剂，可以减轻小鼠Aristolochic I诱导的肝脏和肾脏损伤
Skullcapflavone II, a novel NQO1 inhibitor, alleviates aristolochic acid I-induced liver and kidney injury in mice
影响因子:8.40000
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2023 Jul
作者:
Ya-Ping Dong, Shu-Zhen Chen, Hui-Si He, Zhuo-Ran Sun, Li-Xuan Jiang, Yan-Qiu Gu, Ying Zhang, Fei Feng, Chun Chen, Zhe-Cai Fan, Xiao-Fei Chen, Wen Wen, Hong-Yang Wang
摘要
aristolochicI I（AAI）是一种已建立的肾毒素和人类致癌物。胞质NAD（P）H喹酮氧化还原酶1（NQO1）在硝基胆道酸的硝基还原中起重要作用，从而导致Aristoloactam和AA-DNA加合物的产生。有效的NQO1抑制剂Dicoumarol的应用受到威胁生命的副作用的限制，作为抗凝剂和随后的出血并发症。由于市场中仍然有含有AAI的传统药物，因此迫切需要新型的NQO1抑制剂来减轻AAI暴露的毒性。在这项研究中，我们采用了综合的2D NQO1生物色谱图来筛选可以与NQO1蛋白结合的候选化合物。四种化合物，即Skullcapflavone II（SFII），牛角素A，Wogonin和Tectochrysin从Baicalensis筛选出来。其中，SFII是具有结合亲和力（KD =4.198μmol/L）和抑制活性（IC50 =2.87μmol/L）的最有希望的NQO1抑制剂。在人正常肝细胞系（L02）和人肾近端上皮细胞系（HK-2）中，SFII显着缓解了AAI诱导的DNA损伤和凋亡。在成年小鼠中，口服SFII剂量依赖性地改善AAI诱导的肾纤维化和功能障碍。在婴儿小鼠中，口服SFII抑制AAI诱导的肝细胞癌的起始。此外，SFII的给药不影响成年小鼠的凝血功能。总之，SFII被确定为一种新型的NQO1抑制剂，可能会阻碍AAI对肾脏和肝脏的风险而没有明显的副作用。
Abstract
Aristolochic acid I (AAI) is a well established nephrotoxin and human carcinogen. Cytosolic NAD(P)H quinone oxidoreductase 1 (NQO1) plays an important role in the nitro reduction of aristolochic acids, leading to production of aristoloactam and AA-DNA adduct. Application of a potent NQO1 inhibitor dicoumarol is limited by its life-threatening side effect as an anticoagulant and the subsequent hemorrhagic complications. As traditional medicines containing AAI remain available in the market, novel NQO1 inhibitors are urgently needed to attenuate the toxicity of AAI exposure. In this study, we employed comprehensive 2D NQO1 biochromatography to screen candidate compounds that could bind with NQO1 protein. Four compounds, i.e., skullcapflavone II (SFII), oroxylin A, wogonin and tectochrysin were screened out from Scutellaria baicalensis. Among them, SFII was the most promising NQO1 inhibitor with a binding affinity (KD = 4.198 μmol/L) and inhibitory activity (IC50 = 2.87 μmol/L). In human normal liver cell line (L02) and human renal proximal tubular epithelial cell line (HK-2), SFII significantly alleviated AAI-induced DNA damage and apoptosis. In adult mice, oral administration of SFII dose-dependently ameliorated AAI-induced renal fibrosis and dysfunction. In infant mice, oral administration of SFII suppressed AAI-induced hepatocellular carcinoma initiation. Moreover, administration of SFII did not affect the coagulation function in short term in adult mice. In conclusion, SFII has been identified as a novel NQO1 inhibitor that might impede the risk of AAI to kidney and liver without obvious side effect.