State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Department of Drug Metabolism, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Department of Pharmacy, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Food Chem Toxicol. 2024 Nov;193:114983. doi: 10.1016/j.fct.2024.114983. Epub 2024 Sep 6.
Organic cation transporter 1 (OCT1, gene symbol: SLC22A1) is mainly responsible for the hepatic uptake of various cationic drugs, closely associated with drug-induced liver injury (DILI). Screening and identifying potent OCT1 inhibitors with little toxicity in natural products is of great value in alleviating OCT1-mediated liver injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions (FDIs). Our objective was to investigate potential inhibitors of OCT1 from 96 flavonoids, evaluate the hepatoprotective effects on retrorsine-induced liver injury, and clarify the structure-activity relationships of flavonoids with OCT1. Thirteen flavonoids exhibited significant inhibition (>50%) on OCT1 in OCT1-HEK293 cells. Among them, the five strongest flavonoid inhibitors (IC < 10 μM), including α-naphthoflavone, apigenin, 6-hydroxyflavone, luteolin, and isosilybin markedly decreased oxaliplatin-induced cytotoxicity. In retrorsine-induced liver injury models, they also reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to different levels, the best of which was 6-hydroxyflavone. The pharmacophore model clarified that hydrogen bond acceptors at the 4,8,5' position might play a vital role in the inhibitory effect of flavonoids on OCT1. Taken together, our findings would pave the way to predicting the potential risks of flavonoid-related FDIs in humans and optimizing flavonoid structure to alleviate OCT1-mediated liver injury.
有机阳离子转运蛋白 1（OCT1，基因符号：SLC22A1）主要负责各种阳离子药物的肝脏摄取，与药物性肝损伤（DILI）密切相关。从天然产物中筛选和鉴定毒性小的有效 OCT1 抑制剂，对于缓解 OCT1 介导的肝损伤具有重要价值。黄酮类化合物是一类常见于食品和草药产品中的多酚类化合物，已被报道会引起转运体介导的食物/草药-药物相互作用（FDIs）。我们的目的是从 96 种黄酮类化合物中筛选潜在的 OCT1 抑制剂，评估其对 retrorsine 诱导的肝损伤的保护作用，并阐明黄酮类化合物与 OCT1 的构效关系。13 种黄酮类化合物对 OCT1-HEK293 细胞中的 OCT1 表现出显著的抑制作用（>50%）。其中，五种最强的黄酮类化合物抑制剂（IC<10μM），包括 α-萘黄酮、芹菜素、6-羟基黄酮、木樨草素和异槲皮苷，明显降低了奥沙利铂诱导的细胞毒性。在 retrorsine 诱导的肝损伤模型中，它们也将丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）降低到不同的水平，其中效果最好的是 6-羟基黄酮。药效团模型阐明了 4、8、5' 位的氢键受体可能在黄酮类化合物对 OCT1 的抑制作用中发挥重要作用。综上所述，我们的研究结果将为预测黄酮类化合物相关 FDIs 对人类的潜在风险铺平道路，并优化黄酮类化合物结构以缓解 OCT1 介导的肝损伤。
