Dihydrorotenone is an insecticide and irreversible inhibitor of mitochondrial complex I and can cross the blood-brain barrier [1]. Dihydrorotenone binds to and inhibits the complex I in the electron transport chain, thus inhibiting mitochondrial function and decreasing ATP production[2]. Dihydrorotenone can be labeled for use in radioautography to investigate the unique distribution of complex I in the brain[3].
In vitro, Dihydrorotenone treatment at 20µM for 24 hours triggered endoplasmic reticulum stress and activated the p38 signaling pathway, leading to apoptosis of KMS11 cells[4]. Treatment with 15µM Dihydrorotenone for 24 hours inhibited the expression of cell cycle proteins, causing LP1 cells to be arrested in the G0/G1 phase and reducing the phosphorylation levels of AKT and ERK[5]. After 2 weeks of treatment with 1µM Dihydrorotenone, the expressions of FSP1, PDGFRα and PDGFRβ in SCAF#36 cells significantly decreased, the expression of pro-inflammatory cytokine genes was significantly downregulated, and the cell viability significantly declined[6].
References:
[1] Ambrose A M, Christensen H E, Rather L J. Toxicological and pharmacological studies on dihydrorotenone[J]. Journal of the American Pharmaceutical Association (Scientific ed.), 1953, 42(6): 364-366.
[2] Talpade D J, Greene J G, Higgins Jr D S, et al. In vivo labeling of mitochondrial complex I (NADH: ubiquinoneoxidoreductase) in rat brain using [3H] dihydrorotenone[J]. Journal of neurochemistry, 2000, 75(6): 2611-2621.
[3] Greenamyre J T, Higgins D S, Eller R V. Quantitative autoradiography of dihydrorotenone binding to complex I of the electron transport chain[J]. Journal of neurochemistry, 1992, 59(2): 746-749.
[4] Zhang J, Tang J, Cao B, et al. The natural pesticide dihydrorotenone induces human plasma cell apoptosis by triggering endoplasmic reticulum stress and activating p38 signaling pathway[J]. PloS one, 2013, 8(7): e69911.
[5] Xu X, Zhang J, Han K, et al. Natural pesticide dihydrorotenone arrests human plasma cancer cells at the G0/G1 phase of the cell cycle[J]. Journal of Biochemical and Molecular Toxicology, 2014, 28(5): 232-238.
[6] Lee E, Yeo S Y, Lee K W, et al. New screening system using Twist1 promoter activity identifies dihydrorotenone as a potent drug targeting cancer-associated fibroblasts[J]. Scientific Reports, 2020, 10(1): 7058.
Dihydrorotenone是一种杀虫剂，是线粒体复合物I的不可逆抑制剂，并且能够穿过血脑屏障[1]。Dihydrorotenone结合并抑制电子传递链中的复合物I，从而抑制线粒体功能并减少ATP的产生[2]。Dihydrorotenone可被标记用于放射自显影，以研究复合物I在大脑中的独特分布[3]。
在体外，使用20µM的Dihydrorotenone处理24小时，引发了内质网应激并激活了p38信号通路，导致KMS11细胞凋亡[4]。使用15µM的Dihydrorotenone处理24小时，抑制了细胞周期蛋白的表达，导致LP1细胞停滞在G0/G1期，并降低了AKT和ERK的磷酸化水平[5]。使用1µM的Dihydrorotenone处理2周后，SCAF#36细胞中FSP1、PDGFRα和PDGFRβ的表达显著下降，促炎细胞因子基因的表达显著下调，细胞活力明显降低[6]。