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Toxicity and toxicokinetics of the ethanol extract of Zuojin formula
BACKGROUND: Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377102/ https://www.ncbi.nlm.nih.gov/pubmed/35971113 http://dx.doi.org/10.1186/s12906-022-03684-0 |
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author | Wang, Shuo Zhang, Tao Liu, Xiaoyan Yang, Zheng Li, Ludi Shan, Danping Gao, Yadong Li, Yingzi Li, Yanying Zhang, Youbo Wang, Qi |
author_facet | Wang, Shuo Zhang, Tao Liu, Xiaoyan Yang, Zheng Li, Ludi Shan, Danping Gao, Yadong Li, Yingzi Li, Yanying Zhang, Youbo Wang, Qi |
author_sort | Wang, Shuo |
collection | PubMed |
description | BACKGROUND: Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms. METHODS: Sprague–Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms. RESULTS: Compared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female). CONCLUSIONS: TAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-022-03684-0. |
format | Online Article Text |
id | pubmed-9377102 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-93771022022-08-16 Toxicity and toxicokinetics of the ethanol extract of Zuojin formula Wang, Shuo Zhang, Tao Liu, Xiaoyan Yang, Zheng Li, Ludi Shan, Danping Gao, Yadong Li, Yingzi Li, Yanying Zhang, Youbo Wang, Qi BMC Complement Med Ther Research BACKGROUND: Zuojin formula, a traditional Chinese medicine, comprises Coptis chinensis and Evodia rutaecarpa. In our previous study, the total alkaloid extract from Zuojin formula (TAZF) showed potent and improved efficacy. However, its safety and toxicokinetics remain unknown. The objective of this study was to evaluate the safety of repeated administrations of TAZF and investigate the internal exposure of the main components and its relationship with toxic symptoms. METHODS: Sprague–Dawley rats were orally administered TAZF at 0.4, 1.2 and 3.7 g/kg for 28 days, which was followed by a 14-day recovery period. The toxic effects were evaluated weekly by assessing body weight changes, food intake, blood biochemistry and haematological indices, organ weights and histological changes. A total of eight components were detected, including berberine, coptisine, epiberberine, palmatine, jatrorrhizine, columbamine, evodiamine, and rutaecarpine. The toxicokinetic profiles of the eight components were investigated after single and repeated administrations. Linear mixed effect models were applied to analyse the associations between internal exposure and toxic symptoms. Network pharmacology analysis was applied to explore the potential toxic mechanisms. RESULTS: Compared with the vehicle group, the rats in the low- and medium-dose groups did not show noticeable abnormal changes, while rats in the high-dose group exhibited inhibition of weight gain, a slight reduction in food consumption, abdominal bloating and atrophy of the splenic white pulp during drug administration. The concentration of berberine in plasma was the highest among all compounds. Epiberberine was found to be associated with the inhibition of weight gain. Network pharmacology analysis suggested that the alkaloids might cause abdominal bloating by affecting the proliferation of smooth muscle cells. The benchmark dose lower confidence limits (based on body weight inhibition) of TAZF were 1.27 g/kg (male) and 1.91 g/kg (female). CONCLUSIONS: TAZF has no notable liver or kidney toxicity but carries risks of gastrointestinal and immune toxicity at high doses. Alkaloids from Coptis chinensis are the main plasma components related to the toxic effects of TAZF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12906-022-03684-0. BioMed Central 2022-08-15 /pmc/articles/PMC9377102/ /pubmed/35971113 http://dx.doi.org/10.1186/s12906-022-03684-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Wang, Shuo Zhang, Tao Liu, Xiaoyan Yang, Zheng Li, Ludi Shan, Danping Gao, Yadong Li, Yingzi Li, Yanying Zhang, Youbo Wang, Qi Toxicity and toxicokinetics of the ethanol extract of Zuojin formula |
title | Toxicity and toxicokinetics of the ethanol extract of Zuojin formula |
title_full | Toxicity and toxicokinetics of the ethanol extract of Zuojin formula |
title_fullStr | Toxicity and toxicokinetics of the ethanol extract of Zuojin formula |
title_full_unstemmed | Toxicity and toxicokinetics of the ethanol extract of Zuojin formula |
title_short | Toxicity and toxicokinetics of the ethanol extract of Zuojin formula |
title_sort | toxicity and toxicokinetics of the ethanol extract of zuojin formula |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377102/ https://www.ncbi.nlm.nih.gov/pubmed/35971113 http://dx.doi.org/10.1186/s12906-022-03684-0 |
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