School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, Hong Kong.
Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines Between Shanghai Institute of Materia Medica, Chinese Academy of Sciences and The Chinese University of Hong Kong, Hong Kong, People's Republic of China.
Arch Toxicol. 2017 Dec;91(12):3913-3925. doi: 10.1007/s00204-017-2013-y. Epub 2017 Jun 15.
Pyrrolizidine alkaloids (PAs) are among the most potent phytotoxins widely distributed in plant species around the world. PA is one of the major causes responsible for the development of hepatic sinusoidal obstruction syndrome (HSOS) and exerts hepatotoxicity via metabolic activation to form the reactive metabolites, which bind with cellular proteins to generate pyrrole-protein adducts, leading to hepatotoxicity. PA N-oxides coexist with their corresponding PAs in plants with varied quantities, sometimes even higher than that of PAs, but the toxicity of PA N-oxides remains unclear. The current study unequivocally identified PA N-oxides as the sole or predominant form of PAs in 18 Gynura segetum herbal samples ingested by patients with liver damage. For the first time, PA N-oxides were recorded to induce HSOS in human. PA N-oxide-induced hepatotoxicity was further confirmed on mice orally dosed of herbal extract containing 170 μmol PA N-oxides/kg/day, with its hepatotoxicity similar to but potency much lower than the corresponding PAs. Furthermore, toxicokinetic study after a single oral dose of senecionine N-oxide (55 μmol/kg) on rats revealed the toxic mechanism that PA N-oxides induced hepatotoxicity via their biotransformation to the corresponding PAs followed by the metabolic activation to form pyrrole-protein adducts. The remarkable differences in toxicokinetic profiles of PAs and PA N-oxides were found and attributed to their significantly different hepatotoxic potency. The findings of PA N-oxide-induced hepatotoxicity in humans and rodents suggested that the contents of both PAs and PA N-oxides present in herbs and foods should be regulated and controlled in use.
吡咯里西啶生物碱（PA）是世界范围内广泛分布于植物物种中的最有效植物毒素之一。PA 是导致肝窦阻塞综合征（HSOS）发展的主要原因之一，通过代谢激活形成反应性代谢物发挥其肝毒性，这些代谢物与细胞蛋白结合生成吡咯蛋白加合物，导致肝毒性。PA N-氧化物与植物中的相应 PA 共存，其含量变化较大，有时甚至高于 PA，但 PA N-氧化物的毒性仍不清楚。本研究明确鉴定出 18 种 Gynura segetum 草药样本中的 PA N-氧化物是患者肝损伤中唯一或主要形式的 PA。首次记录到 PA N-氧化物在人体内诱导 HSOS。通过口服给予含有 170 μmol PA N-氧化物/公斤/天的草药提取物的小鼠，进一步证实了 PA N-氧化物引起的肝毒性，其肝毒性与相应的 PA 相似，但效力远低于相应的 PA。此外，大鼠单次口服氧化苦参碱（55 μmol/kg）后的毒代动力学研究揭示了 PA N-氧化物通过其生物转化为相应的 PA 诱导肝毒性，然后通过代谢激活形成吡咯蛋白加合物的毒性机制。发现 PA 和 PA N-氧化物的毒代动力学特征存在显著差异，这归因于它们明显不同的肝毒性效力。在人类和啮齿动物中发现 PA N-氧化物诱导的肝毒性表明，草药和食物中存在的 PA 和 PA N-氧化物的含量应在使用中受到监管和控制。
