Chronotoxicity ofSemen Strychniis associated with circadian metabolism and transport in mice

التفاصيل البيبلوغرافية
العنوان: Chronotoxicity ofSemen Strychniis associated with circadian metabolism and transport in mice
المؤلفون: Yanke Lin, Baojian Wu, Yue Zhao, Lu Gao, Huijie Xing, Danyi Lu, Luomin Lin, Shuai Wang
المصدر: Journal of Pharmacy and Pharmacology. 73:398-409
بيانات النشر: Oxford University Press (OUP), 2020.
سنة النشر: 2020
مصطلحات موضوعية: Male, Time Factors, Pharmaceutical Science, Pharmacology, 030226 pharmacology & pharmacy, Nephrotoxicity, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Circadian Clocks, Microsomes, medicine, Animals, Circadian rhythm, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Brucine, Plant Extracts, Chemistry, Neurotoxicity, ARNTL Transcription Factors, Strychnos nux-vomica, Biological Transport, Strychnine, medicine.disease, Circadian Rhythm, Mice, Inbred C57BL, Toxicity, Neurotoxicity Syndromes, Drug metabolism
الوصف: ObjectivesWe aimed to determine the circadian responses of mice to Semen Strychni and to investigate the role of pharmacokinetics in generating chronotoxicity.MethodsTotal extract of Semen Strychni was administered by oral gavage to wild-type (WT) and Bmal1−/− (a circadian clock-deficient model) mice at different circadian time points for toxicity (including survival) and pharmacokinetic characterization. Nephrotoxicity and neurotoxicity were evaluated by measuring plasma creatinine and creatine kinase BB (CK-BB), respectively. Drug metabolism and transport assays were performed using liver/intestine microsomes and everted gut sacs, respectively.Key findingsSemen Strychni nephrotoxicity and neurotoxicity as well as animal survival displayed significant circadian rhythms (the highest level of toxicity was observed at ZT18 and the lowest level at ZT2 to ZT6). According to pharmacokinetic experiments, herb dosing at ZT18 generated higher plasma concentrations (and systemic exposure) of strychnine and brucine (two toxic constituents) compared with ZT6 dosing. This was accompanied by reduced formation of both dihydroxystrychnine and strychnine glucuronide (two strychnine metabolites) at ZT18. Bmal1 ablation sensitized mice to Semen Strychni-induced toxicity (with increased levels of plasma creatinine and CK-BB) and abolished the time dependency of toxicity. Metabolism of Semen Strychni (strychnine and brucine) in the liver and intestine microsomes of WT mice was more extensive at ZT6 than at ZT18. These time differences in hepatic and intestinal metabolism were lost in Bmal1−/− mice. Additionally, the intestinal efflux transport of Semen Strychni (strychnine and brucine) was more extensive at ZT6 than ZT18 in WT mice. However, the time-varying transport difference was abolished in Bmal1−/− mice.ConclusionsCircadian responses of mice to Semen Strychni are associated with time-varying efflux transport and metabolism regulated by the circadian clock (Bmal1). Our findings may have implications for optimizing phytotherapy with Semen Strychni via timed delivery.
تدمد: 2042-7158
0022-3573
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::13c492b3818c951ca69383e5b2054234
https://doi.org/10.1093/jpp/rgaa007
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....13c492b3818c951ca69383e5b2054234
قاعدة البيانات: OpenAIRE