吡咯里西啶生物碱（PAs）是中草药中一类较常见的肝毒性成分，其主要结构类型包括retronecine型和otonecine型。目前，对otonecine型PAs及其相关中草药的代谢规律、致（解）毒机制的研究仍较少或未能深入。Clivorine是一具有代表性的otonecine型PA。我们前期研究发现，该碱受微粒体中多种代谢酶的作用，并可能通过多种途径（如：坏死、凋亡和自噬）导致肝细胞损伤，提示了otonecine型PAs体内代谢与毒性的复杂性和多样性。本项目拟对此现象进一步展开研究，力图深入地认识其代谢规律及分子毒理机制的多样性；并在此基础之上，以含该类成分的川紫菀药材为范例，通过PAs化学指纹、体内外代谢指纹、代谢组学分析和基于中药整体论多组分整合毒效/毒代动力学特征的解析，以了解该药材潜在毒性的物质基础及可能的作用机制，为进一步系统评价该药材的用药风险和指导临床安全用药提供科学依据。

Pyrrolizidine alkaloids (PAs) are one of the most common naturally-occurring phytotoxins. The toxic PAs usually include retronecine and otonecine types. Both types have been successively found in many traditional Chinese medicinal herbs (CMHs), which structures, metabolism and toxic mechanism have been studied. However, most studies focused on the retronecine-type PAs, studies on the otonecine-type PAs and related CMHs are largely underappreciated. Clivorine is a representative otonecine-type PA found in many CMHs. In our previous studies, clivorine could be metabolized by various enzymes in microsomes and induce liver cell damage through diverse molecular pathways, such as necrosis, apoptosis and autophagy, which may be attributed to the complexity and diversity of the metabolism and toxicity of otonecine-type PAs in vivo. As for the otonecine-type PA-containing CMHs, it may be the more likely case. In this project, both metabolic and the molecular toxicological mechanisms of the otonecine-type PAs will be further studied using clivorine as an example. Furthermore, Chuan Zi Wan (Ligulariae Radix et Rhizoma), which contain the otonecine-type PAs, will be used as the paradigm and studied by chemical and metabolic fingerprints of PAs, analyses of metabolomics and integrated TD/TK characteristics, so as to uncover the real substances and mechanism responsible for its potential toxicity and provide the scientific bases for further comprehensive and systematic evaluation and better understanding of the safety of this herb in Chinese medical practices.