Diurnal hepatic CYP3A11 contributes to chronotoxicity of the pyrrolizidine alkaloid retrorsine in mice
| العنوان: | Diurnal hepatic CYP3A11 contributes to chronotoxicity of the pyrrolizidine alkaloid retrorsine in mice |
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| المؤلفون: | Min Chen, Baojian Wu, Danyi Lu, Pei Yu, Zhigang Wang, Haiman Xu, Li Zhang, Li Guo |
| المصدر: | Xenobiotica. 51:1019-1028 |
| بيانات النشر: | Informa UK Limited, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Pyrrolizidine alkaloid, Health, Toxicology and Mutagenesis, Metabolite, Pharmacology, Toxicology, behavioral disciplines and activities, Biochemistry, Mice, chemistry.chemical_compound, Circadian Clocks, parasitic diseases, Zeitgeber, Animals, Cytochrome P-450 CYP3A, Circadian rhythm, Pyrrolizidine Alkaloids, musculoskeletal, neural, and ocular physiology, Membrane Proteins, Alanine Transaminase, General Medicine, Acute toxicity, Circadian Rhythm, Liver, chemistry, Toxicity, Pyrrolizidine, psychological phenomena and processes, Drug metabolism |
| الوصف: | 1. Retrorsine (RTS) is a pyrrolizidine alkaloid (distributed in many medicinal plants) that has significant hepatotoxicity. Here, we aimed to determine the daily variations in RTS hepatotoxicity (chronotoxicity) in mice, and to investigate the role of metabolism in generating RTS chronotoxicity.2. Acute toxicity and pharmacokinetic studies were performed with mice after RTS administration at different times of the day. Hepatotoxicity was assessed by measuring plasma ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels. mRNA and proteins were determined by qPCR and Western blotting, respectively. Time-dependent in vitro metabolism of RTS was assessed by using mouse liver microsomes.3. We found that RTS toxicity was more severe in the dark phase (zeitgeber time 14 or ZT14 and ZT18) than in the light phase (ZT2 and ZT6). This chronotoxicity was associated with a dosing time difference in the systemic exposures of RTS and a pyrrolic ester metabolite (a cause of hepatotoxicity, measured by the levels of pyrrole-GSH conjugate and pyrrole-protein adducts due to a high chemical reactivity). Moreover, the CYP3A11 (a major enzyme for RTS bioactivation) inhibitor ketoconazole decreased the production of pyrrole-GSH conjugate and abrogated diurnal rhythm in RTS metabolism. In addition, E4bp4 (a circadian regulator of Cyp3a11) ablation abolished the rhythm of CYP3A11 expression and abrogated the dosing time-dependency of RTS toxicity.4. In conclusion, RTS chronotoxicity in mice was attributed to time-varying hepatic metabolism regulated by the circadian clock. Our findings have implications for reducing pyrrolizidine alkaloid-induced toxicity via a chronotherapeutic approach. |
| تدمد: | 1366-5928 0049-8254 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f644d4e9209e92513119d0c98ce38415 https://doi.org/10.1080/00498254.2021.1950867 |
| رقم الأكسشن: | edsair.doi.dedup.....f644d4e9209e92513119d0c98ce38415 |
| قاعدة البيانات: | OpenAIRE |
PDF full text from Publisher | تدمد: | 13665928 00498254 |
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