Protein cross-linking in primary cultured mouse hepatocytes by dehydropyrrolizidine alkaloids: Structure–toxicity relationship. (30th October 2020)

• Record Type: Journal Article
• Authors: Xiong, Fen; Jiang, Kaiyuan; Chen, Yan; Ju, Zhengcai; Yang, Li; Xiong, Aizhen; Wang, Zhengtao
• Is Part Of: Toxicon. Volume 186(2020)
• Page Start: 4
• Page End: 11
• Publication Date: 2020-10-30
• Subjects: Pyrrolizidine alkaloids -- Pyrrole-protein adducts -- Cell viability -- Structure-toxicity relationship -- Primary cultured mouse hepatocytes -- Metabolic activation; CCK-8 Cell Counting Kit-8 -- CYP450 cytochrome P450 -- DABA 4-dimethylaminobenzaldehyde -- DMSO dimethyl sulfoxide -- HSOS hepatic sinusoidal obstruction syndrome -- MRM multiple reaction monitoring -- OTO-PA otonecine type pyrrolizidine alkaloid -- PA pyrrolizidine alkaloid -- PLA-PA platynecine type pyrrolizidine alkaloid -- PPA pyrrole-protein adduct -- RET N-oxide-PA N-oxide of retronecine type pyrrolizidine alkaloid -- RET-PA retronecine type pyrrolizidine alkaloid; Toxins -- Periodicals; Venom -- Periodicals; 615.9
• DOI: 10.1016/j.toxicon.2020.07.015
• Languages: English
• ISSNs: 0041-0101

Abstract

Abstract: Pyrrolizidine alkaloids (PAs) are natural toxins found in about 3%–5% of flowering plants. Dehydropyrrolizidine alkaloids contain a double bond in 1, 2-position of the necine bases, including retronecine type PAs (RET-PAs) and their N -oxides (RET N -oxide-PAs), and otonecine type PAs (OTO-PAs), and are known for their significant hepatotoxicity. Most dehydropyrrolizidine alkaloids are metabolically activated by cytochrome P450 (CYP450) enzymes to generate active pyrroles, which further bind to proteins to form pyrrole–protein adducts (PPAs). Methods for predicting PA-induced liver injury are generally performed on in vitro models with extremely low activities of CYP450 enzymes, which is different from the situation in vivo . In this regard, primary cultured mouse hepatocytes, which showed comparable CYP450 activity with the in vivo models, were applied to illustrate the structure–toxicity relationship of 13 dehydropyrrolizidine alkaloids, namely, eight RET-PAs, three RET N -oxide-PAs, and two OTO-PAs. PA-induced cytotoxicity and PA-generated PPAs were analyzed in primary mouse hepatocytes treated with different PAs. Results showed that PA-induced toxicity was correlated with the amount of PA-generated PPAs. RET-PAs and OTO-PAs were generally more toxic than RET N -oxide-PAs and generated higher amount of PPAs. PPAs were utilized to evaluate the efficiency of metabolic activation and predict the toxic potencies of dehydropyrrolizidine alkaloids. The proposed model could be a new approach for toxicity evaluation and risk control of exposure to PAs. Graphical abstract: Image 1 Highlights: Structure-toxicity relationship of 13 pyrrolizidine alkaloids is investigated. Pyrrole-protein adducts are generated structure- and dose-dependently. A new approach for risk control of exposure to pyrrolizidine alkaloids is proposed.