Fan Yilei, Huang Yingyu, Zhou Yi, Ke Xing, Tian Yimei, Zheng Siyue, Sun Yang, Huang Zhongping, Zhou Jing, Wu Li
Key Laboratory of Drug Prevention and Control Technology of Zhejiang Province, Zhejiang Police College, Hangzhou 310053, China; College of Pharmaceutical Science & Green Pharmaceutical Collaborative Innovation Center of Yangtze River Delta Region, Zhejiang University of Technology, Hangzhou 310053, China.
Department of Food Science and Nutrition, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China.
Ecotoxicol Environ Saf. 2024 Dec;288:117375. doi: 10.1016/j.ecoenv.2024.117375. Epub 2024 Nov 26.
ADB-BUTINACA, as a new psychoactive substance, can induce physical and psychological dependence. However, the systemic biological impact of ADB-BUTINACA on hepatic metabolomics remains uncertain. The metabolic spectrum in rat livers following exposure to three varying doses of ADB-BUTINACA (0.1, 1, and 5 mg/kg·bw) were analyzed using ultra-high-performance liquid chromatography coupled with high-resolution quadrupole-orbitrap mass spectrometry and molecular docking techniques. Non-target metabolomic technology demonstrated that ADB-BUTINACA induced significant changes in 42 metabolites and disturbed 11 metabolic pathways especially the taurine and hypotaurine metabolism, β-alanine metabolism, and arachidonic acid metabolism, implicates the potential for ADB-BUTINACA to induce not merely cardiac dysfunction but also neurological anomalies. Molecular docking into the hepatotoxic targets of ADB-BUTINACA unveiled its potential for competitive binding with pantetheinase. This interaction may disrupt the coenzyme A (CoA) synthesis pathway, resulting in energy and lipid metabolism imbalances, and ultimately causing hepatotoxic effects. Cellular experiments confirmed reduced HepG2 cell viability and elevated reactive oxygen species (ROS) levels in HepG2 and Huh7 cells. These findings align with our metabolomic findings, supporting the hypothesis that ADB-BUTINACA induces hepatotoxicity via oxidative stress, as well as disruptions in energy and lipid metabolism. This work not only broadens the knowledge of ADB-BUTINACA' toxicological profile but also contributes to efforts aimed at diagnosing and preventing ADB-BUTINACA-induced hepatotoxicity.
ADB - 丁丙诺啡作为一种新型精神活性物质，可导致身体和心理依赖。然而，ADB - 丁丙诺啡对肝脏代谢组学的全身生物学影响仍不确定。使用超高效液相色谱结合高分辨率四极杆 - 轨道阱质谱和分子对接技术，分析了大鼠肝脏在暴露于三种不同剂量的ADB - 丁丙诺啡（0.1、1和5 mg/kg·bw）后的代谢谱。非靶向代谢组学技术表明，ADB - 丁丙诺啡引起42种代谢物的显著变化，并扰乱了11条代谢途径，尤其是牛磺酸和亚牛磺酸代谢、β - 丙氨酸代谢和花生四烯酸代谢，这意味着ADB - 丁丙诺啡不仅有诱发心脏功能障碍的可能性，还有诱发神经异常的可能性。对ADB - 丁丙诺啡肝毒性靶点的分子对接揭示了其与泛硫乙胺酶竞争性结合的潜力。这种相互作用可能会破坏辅酶A（CoA）合成途径，导致能量和脂质代谢失衡，最终引起肝毒性作用。细胞实验证实，HepG2细胞活力降低，HepG2和Huh7细胞中的活性氧（ROS）水平升高。这些发现与我们的代谢组学结果一致，支持了ADB - 丁丙诺啡通过氧化应激以及能量和脂质代谢紊乱诱导肝毒性的假设。这项工作不仅拓宽了对ADB - 丁丙诺啡毒理学特征的认识，也有助于诊断和预防ADB - 丁丙诺啡诱导的肝毒性。
