Up-regulation on cytochromes P450 in rat mediated by total alkaloid extract from Corydalis yanhusuo

Yan, Jingjing; He, Xiaolong; Feng, Shan; Zhai, Yiran; Ma, Yetao; Liang, Sheng; Jin, Chunhuan

doi:10.1186/1472-6882-14-306

Cited by 19 publications

(9 citation statements)

References 36 publications

(47 reference statements)

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“…Incubation was done according to the previously described approach 20. The incubation mixtures (200 µL) included 100 mM potassium phosphate buffer (pH 7.4), 0.5 mg/mL mice microsomal protein, and mixture probe substrates for CYP450s (10 µM phenacetin for CYP1A2, 100 µM tolbutamide for CYP2C19, 2.5 µM dextromethorphan for CYP2D6, 20 µM chlorzoxazonefor CYP2E1, 5 µM midazolam for CYP3A4).…”

Section: Methodsmentioning

confidence: 99%

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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

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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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Section: Methodsmentioning

confidence: 99%

“…In our previous study, we have reported a rapid LC–MS/MS method for determination of the activities of five CYP450s in the rat liver 20. Briefly, the HPLC system consisted of an LC-20 AD pump, a DGU-20 A3 degasser, a SIL-20AC autosampler, and a CTO-20A column oven (Shimadzu, Kyoto, Japan).…”

Section: Methodsmentioning

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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“…It also bioactivates several procarcinogens and protoxins, including N-nitrosodimethylamine, benzene, and carbon tetrachloride, to their reactive intermediates [27] . CYP2E1 generates reactive oxygen species (ROS) and substrate-derived radicals, such as oxygen and hydroxyl radicals, which can mediate lipid peroxidation, protein inactivation and DNA damage, leading to cellular injury, especially in the presence of CYP2E1 inducers [28] . Several clinical disorders are associated with changes in the regulation of CYP2E1 and its consequent abnormalities, which include alcoholic liver disease, carcinogenesis, hepatocellular and cholestatic injury, among others [29] .…”

Section: Wwwnaturecom/aps Liu L Et Almentioning

confidence: 99%

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

et al. 2016

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Aim: Caderofloxacin is a new fluoroquinolone that is under phase III clinical trials in China. Here we examined the effects of caderofloxacin on rat hepatic cytochrome P450 (CYP450) isoforms as well as the potential of caderofloxacin interacting with co-administered drugs. Methods: Male rats were treated with caderofloxacin (9 mg/kg, ig) once or twice daily for 14 consecutive days. The effects of caderofloxacin on CYP3A, 2D6, 2C19, 1A2, 2E1 and 2C9 were evaluated using a "cocktail" of 6 probes (midazolam, dextromethorphan, omeprazole, theophylline, chlorzoxazone and diclofenac) injected on d 0 (prior to caderofloxacin exposure) and d 15 (after caderofloxacin exposure). Hepatic microsomes from the caderofloxacin-treated rats were used to assess CYP2E1 activity and chlorzoxazone metabolism. The expression of CYP2E1 mRNA and protein in hepatic microsomes was analyzed with RT-PCR and Western blotting, respectively. Results: Fourteen-day administration of caderofloxacin significantly increased the activity of hepatic CYP2E1, leading to enhanced metabolism of chlorzoxazone. In vitro microsomal study confirmed that CYP2E1 was a major metabolic enzyme involved in chlorzoxazone metabolism, and the 14-d administration of caderofloxacin significantly increased the activity of CYP2E1 in hepatic microsomes, resulting in increased formation of 6-hydroxychlorzoxazone. Furthermore, the 14-d administration of caderofloxacin significantly increased the expression of CYP2E1 mRNA and protein in liver microsomes, which was consistent with the pharmacokinetic results. Conclusion: Fourteen-day administration of caderofloxacin can induce the expression and activity of hepatic CYP2E1 in rats. When caderofloxacin is administered, a potential drug-drug interaction mediated by CYP2E1 induction should be considered.

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“…CYPs are the mixed function oxidase system mainly existing in the liver, and play roles in the metabolism of over 80% drugs [13]. Induction or inhibition of CYP450 is implicated in traditional medicine-induced hepatoprotection and/or hepatotoxicity [14][15][16]. CYP450 genes are regulated by corresponding nuclear receptors, their coordinate regulation affects hepatic phase I and phase II metabolisms [17].…”

Section: Introductionmentioning

confidence: 99%

Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan (Rannasangpei) differs from mercury chloride and methylmercury on hepatic cytochrome P450

Nie¹,

Xu²,

Lu³

et al. 2020

Preprint

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Background: Zuotai (mainly β-HgS)-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei ) is a famous Tibetan medicine for cardiovascular and gastrointestinal diseases. We have shown that 70W protected against CCl 4 hepatotoxicity. CCl 4 is metabolized via cytochrome P450 (CYP450) to produce reactive metabolites. Whether 70W has any effect on CYP450 is unknown and such effects should be compared with mercury compounds for safety evaluation. Methods: Mice were given 70W (0.15-1.5 g/kg, po), Zuotai (30 mg/kg, po), HgCl 2 (33.6 mg/kg, po) and MeHg (3.1 mg/kg, po) for 7 days. Liver RNA and protein were isolated for qPCR and Western-blot analysis. Results: 70W and Zuotai had no effects on hepatic Aryl hydrocarbon receptor (AhR) and CYP1A2, but HgCl 2 and MeHg increased Cyp1a2 mRNA and CYP1A2 protein levels;70W and Zuotai had no effects on constitutive androstane receptor (CAR) ,CYP2B andCYP2E1 expressions, but HgCl 2 increased CAR and Cyp2b10 mRNA, HgCl 2 and MeHg increased CYP2B and CYP2E1 protein expressions; 70W and mercury compounds had no apparent effects on the expression of pregnane X receptor (PXR) and Cyp3a11 mRNA, as well as CYP3A proteins. 70W and mercury compounds had no apparent effects on the expression of peroxisome proliferator-activated receptor alpha (PPARα) and CYP4A; but HgCl 2 tended to increase Cyp4a10 mRNA and CYP4A protein expressions. 70W and Zuotai had no apparent effects on the expression of farnesoid X receptor (FXR) and Cyp7a1 , while HgCl 2 and MeHg increased CYP7A1 expression. Conclusions: Zuotai and Zuotai-containing 70W at clinical doses had minimal influence on hepatic CYPs, and the effects of 70W and Zuotai on CYP and corresponding nuclear receptors are different from HgCl 2 and MeHg.

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Up-regulation on cytochromes P450 in rat mediated by total alkaloid extract from Corydalis yanhusuo

Cited by 19 publications

References 36 publications

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

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

Chronic administration of caderofloxacin, a new fluoroquinolone, increases hepatic CYP2E1 expression and activity in rats

Zuotai (β-HgS)-containing 70 Wei Zhen-Zhu-Wan (Rannasangpei) differs from mercury chloride and methylmercury on hepatic cytochrome P450

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