中国科学院上海药物研究所李川等合作取得重要工作进展。他们研究提出，冰片循环代谢物通过抑制巨噬细胞泡沫形成改善ApoE^−/−小鼠的动脉粥样硬化。相关研究成果2024年10月29日在线发表于《中国药理学报》杂志上。

据介绍，传统药物的转化药理学研究为准确了解药物如何在体内发挥作用发挥治疗作用奠定了基础。冰片是治疗冠心病的常用中药，但其对心血管的具体影响仍知之甚少。

研究发现，冰片中的一种成分异冰片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来评估其抗动脉粥样硬化作用。人类受试者口服含有冰片的草药，并对其血浆样本进行分析，以确定冰片的主要循环化合物，同时还对其体外和小鼠的代谢进行了表征。对所鉴定的化合物进行了评估，以确定其抑制氧化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ApoE^−/−小鼠中评估了重复服用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物，而不是其前体成分冰片和异冰片。这些成分在肠道中被有效吸收，但经历了显著的首过代谢，包括UGT2B7介导的葡萄糖醛酸化分别转化为冰片-2-O-葡萄糖醛酸和异冰片-2-O-葡萄糖醛酸，以及CYP2A6/2B6/3A介导的氧化转化为樟脑。

尽管冰片-2-O-葡萄糖醛酸和异冰片-2-O-葡萄糖醛酸的膜通透性较差，但MRP3/4增强了冰片-2-O-葡萄糖醛酸和异冰片-2-O-葡萄糖醛酸从肝脏流出到全身循环。循环代谢物，特别是它们的组合，在体外显著抑制了氧化低密度脂蛋白诱导的巨噬细胞泡沫细胞形成。亚慢性给药冰片（30 mg·kg^-1·d^-1，i.g.）12周，可显著减小ApoE^−/−小鼠的动脉粥样硬化病变大小并增强斑块稳定性。小鼠全身暴露于冰片代谢物与人类非常相似，这表明冰片在小鼠体内的药效学作用可能也适用于人类。

总之，冰片的心血管益处包括通过其代谢物抑制泡沫细胞形成来减少动脉粥样硬化。这项研究支持口服冰片可以成为一种减少动脉粥样硬化的药物。

附：英文原文

Title: Circulating metabolites of Borneolum syntheticum (Bingpian) ameliorate atherosclerosis in ApoE/ mice via inhibiting macrophage foam-cell formation

Author: 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

Issue&Volume: 2024-10-29

Abstract: 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 (30mg·kg1·d1, 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.

DOI: 10.1038/s41401-024-01406-5

Source: https://www.nature.com/articles/s41401-024-01406-5