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Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity

BACKGROUND: Triptolide, an active ingredient of Chinese medicine plant Tripterygium wilfordii Hook.f., has been shown to exert anti-tumor, immunosuppressive, anti-inflammatory, and anti-fertility pharmacological effects. However, triptolide also causes severe side effects, which are manifested as to...

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Autores principales: Wei, Yuan, Wang, Dujun, Chen, Meng, Ouyang, Zhen, Wang, Shuo, Gu, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913882/
https://www.ncbi.nlm.nih.gov/pubmed/29713369
http://dx.doi.org/10.1186/s13020-018-0179-8
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author Wei, Yuan
Wang, Dujun
Chen, Meng
Ouyang, Zhen
Wang, Shuo
Gu, Jun
author_facet Wei, Yuan
Wang, Dujun
Chen, Meng
Ouyang, Zhen
Wang, Shuo
Gu, Jun
author_sort Wei, Yuan
collection PubMed
description BACKGROUND: Triptolide, an active ingredient of Chinese medicine plant Tripterygium wilfordii Hook.f., has been shown to exert anti-tumor, immunosuppressive, anti-inflammatory, and anti-fertility pharmacological effects. However, triptolide also causes severe side effects, which are manifested as toxicities in multiple organs. The aim of this study was to analyze the role of extrahepatic cytochrome P450 enzymes in triptolide-induced toxicity. METHODS: Xh-CL mouse model with normal liver, but low extrahepatic P450 expression levels was used in this study. Xh-CL mice and C57BL/6 (wildtype, WT) mice were treated with 200 μg/kg triptolide intraperitoneally every other day for 30 days. The serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), creatine (Cre), and blood urea nitrogen (BUN) were detected by kits. The changes of tissue were observed with H&E staining. Two groups of mice (Xh-CL and WT animals), were received a single dose of 1 mg/kg TP by oral gavage for pharmacokinetic analysis. RESULTS: Xh-CL mice displayed higher serum levels of ALT, AST, Cre, and BUN compared to untreated Xh-CL mice. The organ-to-body weight ratio for spleen was high, while that for testes was low. Histopathological changes were observed in multiple organs. However, compared with triptolide-treated WT mice, no significant differences in either blood chemistry or histopathology were recorded. Furthermore, pharmacokinetic studies showed no significant differences between triptolide-treated Xh-CL and WT mice. CONCLUSIONS: Our findings suggest that sub-chronic triptolide treatment can induce toxicities in mouse kidney, spleen, and testis with or without normal local P450 functions. Therefore, extrahepatic P450s play an insignificant role in triptolide-induced toxicity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13020-018-0179-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-59138822018-04-30 Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity Wei, Yuan Wang, Dujun Chen, Meng Ouyang, Zhen Wang, Shuo Gu, Jun Chin Med Research BACKGROUND: Triptolide, an active ingredient of Chinese medicine plant Tripterygium wilfordii Hook.f., has been shown to exert anti-tumor, immunosuppressive, anti-inflammatory, and anti-fertility pharmacological effects. However, triptolide also causes severe side effects, which are manifested as toxicities in multiple organs. The aim of this study was to analyze the role of extrahepatic cytochrome P450 enzymes in triptolide-induced toxicity. METHODS: Xh-CL mouse model with normal liver, but low extrahepatic P450 expression levels was used in this study. Xh-CL mice and C57BL/6 (wildtype, WT) mice were treated with 200 μg/kg triptolide intraperitoneally every other day for 30 days. The serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), creatine (Cre), and blood urea nitrogen (BUN) were detected by kits. The changes of tissue were observed with H&E staining. Two groups of mice (Xh-CL and WT animals), were received a single dose of 1 mg/kg TP by oral gavage for pharmacokinetic analysis. RESULTS: Xh-CL mice displayed higher serum levels of ALT, AST, Cre, and BUN compared to untreated Xh-CL mice. The organ-to-body weight ratio for spleen was high, while that for testes was low. Histopathological changes were observed in multiple organs. However, compared with triptolide-treated WT mice, no significant differences in either blood chemistry or histopathology were recorded. Furthermore, pharmacokinetic studies showed no significant differences between triptolide-treated Xh-CL and WT mice. CONCLUSIONS: Our findings suggest that sub-chronic triptolide treatment can induce toxicities in mouse kidney, spleen, and testis with or without normal local P450 functions. Therefore, extrahepatic P450s play an insignificant role in triptolide-induced toxicity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13020-018-0179-8) contains supplementary material, which is available to authorized users. BioMed Central 2018-04-23 /pmc/articles/PMC5913882/ /pubmed/29713369 http://dx.doi.org/10.1186/s13020-018-0179-8 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Wei, Yuan
Wang, Dujun
Chen, Meng
Ouyang, Zhen
Wang, Shuo
Gu, Jun
Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity
title Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity
title_full Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity
title_fullStr Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity
title_full_unstemmed Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity
title_short Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity
title_sort extrahepatic cytochrome p450s play an insignificant role in triptolide-induced toxicity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913882/
https://www.ncbi.nlm.nih.gov/pubmed/29713369
http://dx.doi.org/10.1186/s13020-018-0179-8
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