Absorption difference between hepatotoxic pyrrolizidine alkaloids and their N-oxides - Mechanism and its potential toxic impact
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摘要Ethnopharmacological relevance: Pyrrolizidine alkaloids (PAs) are a group of phytotoxins widely present in about 3% of flowering plants. Many PA-containing herbal plants can cause liver injury. Our previous studies demonstrated that PA N-oxides are also hepatotoxic, with toxic potency much lower than the corresponding PAs, due to significant differences in their toxicokinetic fates.Aim of study: This study aimed to investigate the oral absorption of PAs and PA N-oxides for better understanding of their significant differences in toxicokinetics and toxic potency.Materials and methods: The oral absorption of PAs and PA N-oxides in rats and in rat in situ single pass intestine perfusion model was investigated. The intestinal permeability and absorption mechanisms of five pairs of PAs and PA N-oxides were evaluated by using Caco-2 monolayer model.Results: The plasma concentrations of total PAs and PA N-oxides within 0-60 min were significantly lower in rats orally treated with a PA N-oxide-containing herbal alkaloid extract than with a PA-containing herbal alkaloid extract at the same dose, indicating that the absorption of PA N-oxides was lower than that of PAs. Using the rat in situ single pass intestine perfusion model, less cumulative amounts of retrorsine N-oxide in mesenteric blood were observed compared to that of retrorsine. In Caco-2 monolayer model, all five PAs showed absorption with P-app A to B values [(1.43-16.26) x 10(-6) cm/s] higher than those of corresponding N-oxides with P-app Ato B values lower than 1.35 x 10(-6) cm/s. A further mechanistic study demonstrated that except for senecionine N-oxide, retrorsine N-oxide, and lycopsamine N-oxide, all PAs and PA N-oxides investigated were absorbed via passive diffusion. While, for these 3 PA N-oxides, in addition to passive diffusion as their primary transportation, efflux transporter-mediated active transportation was also involved but to a less extent with the efflux ratio of 2.31-3.41. Furthermore, a good correlation between lipophilicity and permeability of retronecine-type PAs and their N-oxides with absorption via passive diffusion was observed, demonstrating that PAs have a better oral absorbability than that of the corresponding PA N-oxides.Conclusion: We discovered that among many contributors, the lower intestinal absorption of PA N-oxides was the initiating contributor that caused differences in toxicokinetics and toxic potency between PAs and PA N-oxides.
著者Mengbi YANG, Jiang MA, Jianqing RUAN, Chunyuan ZHANG, Yang YE, Peter Pi-Cheng FU, Ge LIN
期刊名稱Journal of Ethnopharmacology
出版年份2020
月份3
卷號249
出版社Elsevier
文章號碼112421
國際標準期刊號0378-8741
語言英式英語
Web of Science 學科類別Plant Sciences;Chemistry, Medicinal;Integrative & Complementary Medicine;Pharmacology & Pharmacy;Plant Sciences;Pharmacology & Pharmacy;Integrative & Complementary Medicine

上次更新時間 2021-18-09 於 00:00