He Rong-Rong, Ma Chuan-Rui, He Xin, Dong Yan-Xi, Li Hui, Chu Zi-Xuan, Yang Xi-He, Wang Jia-Qi, Wang Ting, Wang Feng-Qing, Du Fei-Fei, Rao Ying, Yu Wen-Xuan, Gao Xiu-Mei, Fan Guan-Wei, Cheng Chen, Li Chuan
Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
Acta Pharmacol Sin. 2025 Mar;46(3):759-776. doi: 10.1038/s41401-024-01406-5. Epub 2024 Oct 29.
Translational pharmacological research on traditional medicines lays the foundation for precisely understanding how the medicines function in the body to deliver therapeutic benefits. Borneolum syntheticum (Bingpian) is commonly used in Chinese herbal medicines for coronary heart disease, but its specific cardiovascular impact remains poorly understood. Isoborneol, a constituent of Bingpian, has been found to reduce lipid accumulation in macrophages in vitro, but its oral bioavailability is limited. This investigation aimed to evaluate anti-atherosclerotic effects of Bingpian, based on understanding its first-pass metabolism. Human subjects orally received an herbal medicine containing Bingpian and their plasma samples were analyzed to identify the major circulating compounds of Bingpian, with the metabolism that was also characterized in vitro and in mice. The identified compounds were evaluated for their ability to inhibit macrophage foam-cell formation induced by oxidized low-density lipoprotein. Furthermore, the anti-atherosclerotic effect of repeatedly dosed Bingpian was assessed in ApoE mice fed a high-fat diet. In human subjects, the major circulating compounds of Bingpian were metabolites, rather than their precursor constituents borneol and isoborneol. These constituents were efficiently absorbed in the intestinal tract but underwent significant first-pass metabolism, involving UGT2B7-mediated glucuronidation into borneol-2-O-glucuronide and isoborneol-2-O-glucuronide, respectively, and CYP2A6/2B6/3A-mediated oxidation both into camphor. Despite their poor membrane permeability, hepatic efflux of borneol-2-O-glucuronide and isoborneol-2-O-glucuronide into the systemic circulation was enhanced by MRP3/4. The circulating metabolites, particularly their combinations, markedly inhibited macrophage foam-cell formation induced by oxidized low-density lipoprotein in vitro. Sub-chronic administration of Bingpian (30 mg·kg·d, i.g.) for 12 weeks significantly decreased atherosclerotic lesion size and enhanced plaque stability in ApoE mice. Systemic exposure to Bingpian metabolites in mice closely resembles that in humans, suggesting that the pharmacodynamic effects of Bingpian in mice are likely applicable to humans. Overall, the cardiovascular benefits of Bingpian involve reducing atherosclerosis by inhibiting foam-cell formation through its metabolites. This investigation supports that oral Bingpian could be a druggable agent for reducing atherosclerosis.
传统药物的转化药理学研究为准确理解药物在体内发挥治疗作用的机制奠定了基础。冰片常用于治疗冠心病的中草药中，但其具体的心血管作用仍知之甚少。冰片的成分异龙脑已被发现可在体外减少巨噬细胞中的脂质积累，但其口服生物利用度有限。本研究旨在基于对冰片首过代谢的了解，评估其抗动脉粥样硬化作用。人类受试者口服含冰片的草药后，分析其血浆样本以鉴定冰片的主要循环化合物，并在体外和小鼠体内对其代谢特征进行了表征。评估所鉴定的化合物抑制氧化型低密度脂蛋白诱导的巨噬细胞泡沫细胞形成的能力。此外，在喂食高脂饮食的载脂蛋白E小鼠中评估了重复给药冰片的抗动脉粥样硬化作用。在人类受试者中，冰片的主要循环化合物是代谢产物，而非其前体成分冰片和异龙脑。这些成分在肠道中被有效吸收，但经历了显著的首过代谢，分别涉及UGT2B7介导的葡萄糖醛酸化生成冰片-2-O-葡萄糖醛酸苷和异龙脑-2-O-葡萄糖醛酸苷，以及CYP2A6/2B6/3A介导的氧化生成樟脑。尽管冰片-2-O-葡萄糖醛酸苷和异龙脑-2-O-葡萄糖醛酸苷的膜通透性较差，但MRP3/4增强了它们从肝脏向体循环的外排。循环代谢产物，特别是它们的组合，在体外显著抑制氧化型低密度脂蛋白诱导的巨噬细胞泡沫细胞形成。在载脂蛋白E小鼠中，连续12周给予冰片（30mg·kg·d，灌胃）可显著减小动脉粥样硬化病变大小并增强斑块稳定性。小鼠体内冰片代谢产物的全身暴露情况与人类相似，表明冰片在小鼠中的药效作用可能适用于人类。总体而言，冰片的心血管益处包括通过其代谢产物抑制泡沫细胞形成来减轻动脉粥样硬化。本研究支持口服冰片可能是一种可用于减轻动脉粥样硬化的药物。
