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.
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Acknowledgements
We would like to thank the support from the Shanghai Key Laboratory of Hepatobiliary Tumor Biology and Military Key Laboratory and Targeting Therapy of Liver Cancer, Second Military Medical University, Shanghai, China. We thank Ms. Lu Chen, Ms. Dan Cao, Ms. Lin-na Guo, and Ms. Shan-hua Tang from International Cooperation Laboratory on Signal Transduction for their technical support. This work was supported by the Ministry of Science and Technology Key Program for “Significant New Drugs Development” (2018ZX09101002, 2018ZX09101002-001-001, 2018ZX09101002-001-002). Funding for this project was also provided by the National Natural Science Foundation of China (81830054, 91859205, 82072600, 81973291, and 82122066). The plan of Shanghai Municipal Health Commission (2022XD036) also provided funding to conduct this project.
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YPD, WW, and HYW designed the study. YPD, SZC, and HSH developed the methodology. YPD, ZRS, YQG, and YZ acquired data. SZC, YPD, HSH, and FF analyzed and interpreted data. YPD, SZC, and LXJ wrote and reviewed the manuscript. ZCF, HSH, and CC provided technical and material support. XFC, WW, and HYW supervised the study.
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Dong, Yp., Chen, Sz., He, Hs. et al. Skullcapflavone II, a novel NQO1 inhibitor, alleviates aristolochic acid I-induced liver and kidney injury in mice. Acta Pharmacol Sin 44, 1429–1441 (2023). https://doi.org/10.1038/s41401-023-01052-3
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DOI: https://doi.org/10.1038/s41401-023-01052-3
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