In vivo effect of Schisandrin B on cytochrome P450 enzyme activity

Li, Wei-Liang; Xin, Hua‐Wen; Ai-rong, YU; Wu, Xiaochun

doi:10.1016/j.phymed.2013.02.005

Cited by 22 publications

(15 citation statements)

References 22 publications

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“…In previous research, shengmai injection, which contains Sch B as an active ingredient, intravenous administrated in rat, Sch B was found to distribute quickly from blood into most tissues, prone to fat and liver specifically, and had accumulation in these tissues[36],which can be explained by its high liposolubility because of structure characteristics. Sch B also has the effect of raising blood concentrations of co-administering immunosuppressive drug and decreasing the total expense of drug, so Sch B should be used carefully under guidance [37]. In summary, our study showed that Sch B has potential as a novel anti-tumor therapeutic strategy for the treatment of gallbladder cancer.…”

Section: Resultsmentioning

confidence: 88%

Schisandrin B Induces Apoptosis and Cell Cycle Arrest of Gallbladder Cancer Cells

Xiang

Wang

et al. 2014

Molecules

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Gallbladder cancer, with high aggressivity and extremely poor prognosis, is the most common malignancy of the bile duct. The main objective of the paper was to investigate the effects of schisandrin B (Sch B) on gallbladder cancer cells and identify the mechanisms underlying its potential anticancer effects. We showed that Sch B inhibited the viability and proliferation of human gallbladder cancer cells in a dose-, time -dependent manner through MTT and colony formation assays, and decrease mitochondrial membrane potential (ΔΨm) at a dose-dependent manner through flow cytometry. Flow cytometry assays also revealed G0/G1 phase arrest and apoptosis in GBC-SD and NOZ cells. Western blot analysis of Sch B-treated cells revealed the upregulation of Bax, cleaved caspase-9, cleaved caspase-3, cleaved PARP and downregulation of Bcl-2, NF-κB, cyclin D1 and CDK-4. Moreover, this drug also inhibited the tumor growth in nude mice carrying OPEN ACCESSMolecules 2014, 19 13236 subcutaneous NOZ tumor xenografts. These data demonstrated that Sch B induced apoptosis in gallbladder cancer cells by regulating apoptosis-related protein expression, and suggests that Sch B may be a promising drug for the treatment of gallbladder cancer.

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Section: Resultsmentioning

confidence: 88%

Schisandrin B Induces Apoptosis and Cell Cycle Arrest of Gallbladder Cancer Cells

Xiang

Wang

et al. 2014

Molecules

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“…Further researches pointed that apart from schisantherin A, other lignan components, such as schisandrin A, schisandrin B, schisandrin C, schisandrol A and schisandrol B, could also inhibit CYP3A-mediated FK506 metabolism in rat; schisandrol B showed the strongest effect in vivo. 41,42 In addition, schisandrol B, schisandrin A and schisandrin B were more efficient than schisandrol A in inducing CYP3A mRNA expression in hepatocytes. 43 Referring to CYP3A, these ligans showed inhibitory effect on CYP3A in vitro but also caused increase of CYP3A content in vivo after multiple-dose administration.…”

Section: Discussionmentioning

confidence: 97%

“… Among them, schisantherin A was proved to display the most potent and competitive inhibitory effect on CYP3A4 in vitro, stronger than that of ketoconazole. Further researches pointed that apart from schisantherin A, other lignan components, such as schisandrin A, schisandrin B, schisandrin C, schisandrol A and schisandrol B, could also inhibit CYP3A‐mediated FK506 metabolism in rat; schisandrol B showed the strongest effect in vivo . In addition, schisandrol B, schisandrin A and schisandrin B were more efficient than schisandrol A in inducing CYP3A mRNA expression in hepatocytes .…”

Section: Discussionmentioning

confidence: 98%

Wuzhi capsule regulates chloroacetaldehyde pharmacokinetics behaviour and alleviates high‐dose cyclophosphamide‐induced nephrotoxicity and neurotoxicity in rats

Chen

Xiong

Hou

et al. 2019

Basic Clin Pharma Tox

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High‐dose cyclophosphamide (HD‐CTX) treatment often leads to severe nephrotoxicity and neurotoxicity, which are mainly caused by one of its metabolites, chloroacetaldehyde (CAA). However, there are no effective antidotes to prevent these side effects. The objective of this study was to evaluate the effect of Wuzhi Capsule (WZC) on the pharmacokinetics of CTX and its metabolites in rats, and the attenuation of CAA induced kidney and brain injuries, which was produced at equimolar with 2‐dechloroethylcyclophosphamide. Rats were treated with single‐ or multiple‐dose of WZC when giving HD‐CTX, and the plasma concentration of CTX and its metabolites were quantitated by UHPLC‐MS/MS Single‐dose, not multiple‐dose of WZC co‐administration (300 mg/kg) significantly reduced Cmax and AUC0→24 h of DC‐CTX by 33.10% and 35.51%, respectively. Biochemical assay suggested oxidative stress was involved in kidney and brain injuries by HD‐CTX, which were attenuated by single‐dose WZC (300 mg/kg) pre‐treatment, with increased glutathione, glutathione peroxidase and superoxide dismutase contents/or activities in both tissues and plasma (P < 0.05). Meanwhile, WZC pre‐treatment could also significantly decrease the plasma levels of creatinine, blood urea nitrogen and malondialdehyde (P < 0.05). Additionally, WZC treatment improved the morphology and pathology condition of the kidneys and brains in rats. In conclusion, single‐dose WZC co‐administration decreased CAA production and exerted protective effect on CTX‐induced oxidative stress in kidney and brain, whereas repetitive WZC co‐administration with CTX was probably not recommended.

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“…Li et al observed that an oral administration of Sch B (2–16 mg/kg) for three consecutive days may significantly inhibit rat hepatic microsomal CYP3A activity in a dose-dependent manner, with a K i value of 16.64 mg/kg 31. Besides, they also demonstrated that Sch B could inhibit the CYP3A activity with IC 50 value at 5.51 µM32 in rat liver microsomes. Similarly, Qin et al reported that one single dose of Sch B (0.024 mM/kg) could increase the tacrolimus bioavailability in rat via inhibiting the P-gp–mediated efflux and CYP3A-mediated metabolism 33.…”

Section: Discussionmentioning

confidence: 99%

Schisandrin B elicits the Keap1-Nrf2 defense system via carbene reactive metabolite which is less harmful to mice liver

Feng¹,

Qiu²,

Zou³

et al. 2018

DDDT

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BackgroundSchisandrin B (Sch B) a main active component of Schisandra chinensis, has been shown to act as a liver protectant via activation of the Nrf2 pathway. Nevertheless, it remains unclear whether its reactive metabolite is responsible for Nrf2 activation; also, the effects of its reactive metabolite on liver function are still unknown.MethodsThe present study determined and identifed the carbene reactive metabolite of Sch B in human and mice liver microsomes. Its roles in activating Nrf2 pathway and modifying macromolecules were further explored in human liver microsomes. Moreover the potential cytotoxicity and hepatoxicity of carbene on HepG-2 and mice were also investigated.ResultsIn the present study, cytochromes P450 (CYP450s) metabolized Sch B to carbene reactive metabolite, which, with the potential to modify peptides, were identifed and observed in human and mice liver microsomes. Moreover, the relevance of carbene in Nrf2 activation was verifed by co-incubation in the presence of CYP450 inhibitors in HepG-2 cells, as well as by molecular docking study of carbene and Keap1. Additionally, the cytotoxicity of Sch B on HepG-2 cells was signifcantly aggravated by CYP450 inducer (with LD50 decreasing from 63 to 21 µM) and signifcantly alleviated by CYP450 inhibitor and glutathione (with LD50 increasing from 63 µM to 200 µM). Besides, after oral administration of mice with Sch B (25–100 mg/kg) for 21 days, only the highest dose induced mild hepatotoxicity, which was accompanied by increasing the aminotransferase activity and centrilobular hepatocellular infltration of lymphocytes. In addition, upregulation of CYP450 activity; Nrf2, NQO-1, and GST expression; and glutathione level was observed in Sch B treatment groups.ConclusionThe present study revealed that CYP450s mediate the conversion of Sch B to carbene, which subsequently binds to Keap1 and elicits Nrf2 pathway, which could further increase the elimination of carbene and thus exhibit a less harmful effect on mice liver.

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In vivo effect of Schisandrin B on cytochrome P450 enzyme activity

Cited by 22 publications

References 22 publications

Schisandrin B Induces Apoptosis and Cell Cycle Arrest of Gallbladder Cancer Cells

Schisandrin B Induces Apoptosis and Cell Cycle Arrest of Gallbladder Cancer Cells

Wuzhi capsule regulates chloroacetaldehyde pharmacokinetics behaviour and alleviates high‐dose cyclophosphamide‐induced nephrotoxicity and neurotoxicity in rats

Schisandrin B elicits the Keap1-Nrf2 defense system via carbene reactive metabolite which is less harmful to mice liver

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