School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
J Ethnopharmacol. 2024 Mar 1;321:117390. doi: 10.1016/j.jep.2023.117390. Epub 2023 Nov 11.
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.
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.
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.
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.
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.
吡咯里西啶生物碱（PAs）是一组植物毒素，存在于全球约 3%的开花植物中。摄入含有 PAs 的草药产品可能导致肝毒性。值得注意的是，毒代动力学（TK）行为，特别是具有相同结构但由不同 PAs 代谢活化生成的吡咯蛋白加合物（PPAs），显著影响结构多样的 PAs 的毒性，因此研究其纯形式优于研究草药提取物中存在的不同 PAs 的混合物，以分层不同 PAs 的毒性强度。然而，先前的研究主要集中在完整 PAs 的 TK 谱的建立上，揭示了较少或没有关于主要 PA 代谢物（PA N-氧化物）和介导 PA 诱导肝毒性的 PPAs 的动力学信息。在这项研究中，PPA 被用作 PA 暴露和 PA 诱导毒性的生物标志物。
本研究旨在研究结构多样的 retronecine 型 PAs： retrorsine（RTS）和 monocrotaline（MCT）以及 otonecine 型 PA：clivorine（CLI）之间的 TK 差异，及其毒性相关代谢物 PPAs 和 PA N-氧化物，作为 retronecine 型 PAs 的主要代谢物，为更准确地评估 PA 暴露风险奠定基础。
采用大鼠静脉（i.v.）或口服（p.o.）给予 20mg/kg 的 PAs 进行 TK 研究。从血浆浓度-时间曲线中确定 PAs 和 PA N-氧化物的主要 TK 参数，并从血浆和红细胞浓度-时间曲线评估 PPAs 的动力学曲线。
在这三种 PAs 中，MCT 的吸收最慢但程度最高，而 RTS 的吸收速度与 CLI 相似，但程度较低。在消除方面，MCT 的消除率与 RTS 相似，但程度在三种 PAs 中最低，而 CLI 的消除速度明显快于 MCT 和 RTS。此外，仅在 retronecine 型 PAs 中发生的 PA N-氧化物的形成在 MCT 处理的大鼠中明显少于 RTS 处理的大鼠。值得注意的是，retronecine 型 RTS 和 MCT 通过口服途径比静脉途径诱导更多的 PPAs，而 otonecine 型 CLI 则表现出相反的趋势。
在大鼠中，结构多样的 PAs 之间存在显著的 TK 差异，不仅包括 PAs，还包括 PA N-氧化物和衍生的蛋白加合物 PPAs，为不同含 PA 草药产品引起的不同肝毒性强度奠定了基础。值得注意的是，我们的研究结果首次揭示，与静脉途径相比，retronecine 型 PAs 的口服给药可能会导致更严重的毒性，这需要进一步深入探讨。
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