背景:吡咯利嗪定生物碱(PA)是存在于全世界约3%的开花植物中的一组植物毒素。摄入含PA的草药产品可能导致肝毒性。值得注意的是,毒物代谢动力学(TK)行为,特别是吡咯-蛋白质加合物(PPAs)具有相同的结构,但产生于不同的PAs的代谢激活,显着影响结构不同的PA的毒性,因此,以纯形式研究它们比提取物更可取,以分层草药提取物中共存的不同PA的毒性效力。然而,以前的研究主要集中在完整PAs的TK概况的建立上,在介导PA诱导的肝毒性的主要PA代谢物(PAN-氧化物)和PPA上显示较少或没有动力学信息。在这项研究中,测量PPA作为PA暴露和PA诱导的毒性的生物标志物。
目的:本研究旨在研究retronecine型PAs的结构多样性PAs之间的TK差异:retrorsine(RTS)和野百合碱(MCT),和羟菜碱型PA:Clivorine(CLI),以及它们的毒性相关代谢产物PPAs和PAN-氧化物,retronecine型PAs的主要代谢产物,建立更准确的PA暴露风险评估。
方法:使用大鼠通过静脉内(i.v.)或口服(p.o.)给予20mg/kg的PAs进行TK研究。从血浆浓度-时间曲线确定了PAs和PAN-氧化物的主要TK参数,从血浆和红细胞浓度-时间曲线评估PPA的动力学曲线。
结果:MCT在三种PA中表现出最慢但最高的吸收程度,而RTS表现出相似的吸收率,其程度低于CLI。为了消除,MCT表现出与RTS相似的消除率,但在三种PA中消除程度最低,CLI的消除速度明显快于MCT和RTS。此外,PAN-氧化物的形成,这只发生在retronecine型PA中,与RTS治疗的大鼠相比,MCT治疗的大鼠明显更少。值得注意的是,retronecine型RTS和MCT通过p.o.比静脉给药途径诱导更多的PPAs,而耳鼻喉素型CLI表现出相反的趋势。
结论:戏剧性的传统知识差异,不仅包括PA,还包括PAN-氧化物和衍生的蛋白质加合物PPAs,在大鼠的结构多样的PA中发现,为不同含PA的草药产品诱导的各种肝毒性奠定了基础。值得注意的是,我们的发现首次发现,与静脉途径相比,口服retronecine型PAs可能会引起更严重的毒性,这值得进一步深入探索。
BACKGROUND: Pyrrolizidine alkaloids (PAs) are a group of phytotoxins present in about 3% of flowering plants worldwide. Ingestion of PA-containing herbal products may lead to hepatotoxicity. Notably, the toxicokinetic (TK) behaviors, especially pyrrole-protein adducts (PPAs) having the same structure but generated from metabolic activation of different PAs, significantly affect the toxicity of structurally diverse PAs, therefore studying them in their pure form is preferable to extracts to stratify toxic potency of different PAs co-existing in herbal extracts. However, previous studies mainly focus on the establishment of TK profiles of the intact PAs, revealing less or no kinetic information on the main PA metabolites (PA N-oxides) and PPAs which mediate PA-induced hepatotoxicity. In this study, PPA was measured as the biomarker of PA exposure and PA-induced toxicity.
OBJECTIVE: This study aims to investigate the TK difference between structurally diverse PAs of retronecine-type PAs: retrorsine (RTS) and monocrotaline (MCT), and otonecine-type PA: clivorine (CLI), and their toxicity-related metabolite PPAs and PA N-oxides, the main metabolite of retronecine-type PAs, for the establishment of a more accurate risk assessment of PAs exposure.
METHODS: The TK studies were conducted using rats through intravenous (i.v.) or oral (p.o.) administration of PAs at 20 mg/kg. The main TK parameters of PAs and PA N-oxides were determined from plasma concentration-time profiles, and the kinetic profiles of PPAs were assessed from both plasma and erythrocyte concentration-time profiles.
RESULTS: MCT demonstrated the slowest but the highest extent of absorption among the three PAs, while RTS demonstrated a similar absorption rate with a lower extent than CLI. For elimination, MCT demonstrated a similar elimination rate as RTS but the lowest extent of elimination among the three PAs, and CLI exhibited significantly faster elimination than MCT and RTS. Moreover, the formation of PA N-oxide, which only occurs in retronecine-type PAs, was remarkably less in MCT-treated rats compared to RTS-treated ones. Of note, the retronecine-type RTS and MCT induced more PPAs via p.o. than i.v. administration route, whereas the otonecine-type CLI showed the opposite trend.
CONCLUSIONS: Dramatic TK differences, including not only PAs but also PA N-oxides and the derived protein adduct PPAs, were found among structurally diverse PAs in rats, laying the basis for varied hepatotoxic potencies induced by different PA-containing herbal products. Notably, our findings for the first time uncovered that oral administration of retronecine-type PAs might cause severer toxicity compared with the intravenous route, which warrants further in-depth exploration.