Bufalin inhibits CYP3A4 activity in vitro and in vivo

Li, Haiyun; Xu, Wen; Zhang, Xi; Zhang, Weidong; Hu, Lifen

doi:10.1038/aps.2009.42

Cited by 12 publications

(8 citation statements)

References 22 publications

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“…Molecules like curcumin, kaempferol, and silibinin have appeared in thousands of scholarly articles, many investigating the molecular targets through which these molecules act (Table ). Over 10 000 targets have been identified, with the purified TCM components typically acting in the 1 to 200 μM concentration range (Table ). − Intriguingly, the targets reported for even a single compound are often unrelated. For instance, curcumin has been reported to inhibit calcium-dependent ATPase, HIV-1 and HIV-2 proteases, human growth factor receptor 2 (HER2), protein kinase A (PKA), protein kinase C (PKC), lipoxygenase, P450 enzymes, tyrosinase, and thioredoxin reductase, among others.…”

Section: Introductionmentioning

confidence: 99%

Colloidal Aggregation and the in Vitro Activity of Traditional Chinese Medicines

et al. 2015

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Traditional Chinese Medicines (TCMs) have been the sole source of therapeutics in China for two millennia. In recent drug discovery efforts, purified components of TCM formulations have shown activity in many in vitro assays, raising concerns of promiscuity. Here, we investigated 14 bioactive small molecules isolated from TCMs for colloidal aggregation. At concentrations commonly used in cell-based or biochemical assay conditions, eight of these compounds formed particles detectable by dynamic light scattering and showed detergent-reversible inhibition against β-lactamase and malate dehydrogenase, two counter-screening enzymes. When tested against their literature-reported molecular targets, three of these eight compounds showed similar reversal of their inhibitory activity in the presence of detergent. For three of the most potent aggregators, contributions to promiscuity via oxidative cycling were investigated; addition of 1 mM DTT had no effect on their activity, which is inconsistent with an oxidative mechanism. TCMs are often active at micromolar concentrations; this study suggests that care must be taken to control for artifactual activity when seeking their primary targets. Implications for the formulation of these molecules are considered.

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Section: Introductionmentioning

confidence: 99%

Colloidal Aggregation and the in Vitro Activity of Traditional Chinese Medicines

et al. 2015

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“…The results demonstrated that ArBu entered the blood rapidly and was detected only after 2 min CYP3A4 was the major metabolic enzyme of bufogenins. Since bufalin was a strong inhibitor of CYP3A4 ( Li et al, 2009 ), ArBu with the same parent nucleus was likely to inhibit CYP3A4. In combination with the results from the heart rate test, it was found that the rats’ heart rates in the 60 mg/kg ArBu-administrated group increased significantly at T max .…”

Section: Resultsmentioning

confidence: 99%

Toxicokinetics of Arenobufagin and its Cardiotoxicity Mechanism Exploration Based on Lipidomics and Proteomics Approaches in Rats

et al. 2021

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Arenobufagin (ArBu), one of the main active bufadienolides of toad venom with cardiotonic effect, analgesic effect, and outstanding anti-tumor potentiality, is also a potential cardiotoxic component. In the present study, the cardiac effect of ArBu and its underlying mechanism were explored by integrating data such as heart rates, toxicokinetics, myocardial enzyme and brain natriuretic peptide (BNP) activity, pathological sections, lipidomics and proteomics. Under different doses, the cardiac effects turned out to be different. The oral dose of 60 mg/kg of ArBu sped up the heart rate. However, 120 mg/kg ArBu mainly reduced the heart rate. Over time, they all returned to normal, consisting of the trend of ArBu concentration-time curve. High concentrations of myocardial enzymes and BNP indicated that ArBu inhibited or impaired the cardiac function of rats. Pathological sections of hearts also showed that ArBu caused myocardial fiber disorder and rupture, in which the high-dose group was more serious. At the same time, serum and heart tissue lipidomics were used to explore the changes in body lipid metabolism under different doses. The data indicated a larger difference in the high-dose ArBu group. There were likewise many significant differences in the proteomics of the heart. Furthermore, a multi-layered network was used to integrate the above information to explore the potential mechanism. Finally, 4 proteins that were shown to be significantly and differentially expressed were validated by targeted proteomics using parallel reaction monitoring (PRM) analysis. Our findings indicated that ArBu behaved as a bidirectional regulation of the heart. The potential mechanism of cardiac action was revealed with the increased dose, which provided a useful reference for the safety of clinical application of ArBu.

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“…CYP3A4 accounts for ~40% of the total cytochrome P450 in human liver microsomes and metabolizes >50% of the clinically used drugs 19. Earlier research has also shown that bufalin had a modest but significant inhibition of CYP3A4 enzyme both in vitro and in vivo 20. As a result, the high CYP3A4 enzyme metabolic capability in liver would be a probable explanation for the extremely high concentration of bufalin and [ 18 F]fluoroethyl bufalin in liver.…”

Section: Discussionmentioning

confidence: 99%

Radiosynthesis and pharmacokinetics of [<sup>18</sup>F]fluoroethyl bufalin in hepatocellular carcinoma-bearing mice

Yang¹,

Liu²,

Huang³

et al. 2017

OTT

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PurposeBufalin, the main component of a Chinese traditional medicine chansu, shows convincing anticancer effects in a lot of tumor cell lines. However, its in vivo behavior is still unclear. This research aimed to evaluate how bufalin was dynamically absorbed after intravenous injection in animal models. We developed a radiosynthesis method of [18F]fluoroethyl bufalin to noninvasively evaluate the tissue biodistribution and pharmacokinetics in hepatocellular carcinoma-bearing mice.Methods[18F]fluoroethyl bufalin was synthesized with conjugation of 18F-CH2CH2OTs and bufalin. The radiochemical purity was proved by the radio-high-performance liquid chromatography (HPLC). The pharmacokinetic studies of [18F]fluoroethyl bufalin were then performed in Institute of Cancer Research (ICR) mice. Furthermore, the biodistribution and metabolism of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing nude mice were studied in vivo by micro-positron emission tomography (micro-PET).ResultsThe radiochemical purity (RCP) of [18F]fluoroethyl bufalin confirmed by radio-HPLC was 99%±0.18%, and [18F]fluoroethyl bufalin showed good in vitro and in vivo stabilities. Blood dynamics of [18F]fluoroethyl bufalin conformed to the two compartments in the ICR mice model. The pharmacokinetic parameters of [18F]fluoroethyl bufalin were calculated by DAS 2.0 software. The area under concentration–time curve (AUC0–t) and the values of clearance (CL) were 540.137 μg/L·min and 0.001 L/min/kg, respectively. The half-life of distribution (t1/2α) and half-life of elimination (t1/2β) were 0.693 and 510.223 min, respectively. Micro-PET imaging showed that [18F]fluoroethyl bufalin was quickly distributed via the blood circulation; the major tissue biodistribution of [18F]fluoroethyl bufalin in HepG2 and SMMC-7721 tumor-bearing mice was liver and bladder.Conclusion[18F]fluoroethyl bufalin was accumulated rapidly in the liver at an early time point (5 min) post injection (pi) and then declined slowly, mainly through both the hepatic pathway and the renal pathway. Our study showed the biodistribution of [18F]fluoroethyl bufalin in micro-PET images and provided visible information for demonstrating the bioactivities of bufalin.

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Bufalin inhibits CYP3A4 activity in vitro and in vivo

Cited by 12 publications

References 22 publications

Colloidal Aggregation and the in Vitro Activity of Traditional Chinese Medicines

Colloidal Aggregation and the in Vitro Activity of Traditional Chinese Medicines

Toxicokinetics of Arenobufagin and its Cardiotoxicity Mechanism Exploration Based on Lipidomics and Proteomics Approaches in Rats

Radiosynthesis and pharmacokinetics of [<sup>18</sup>F]fluoroethyl bufalin in hepatocellular carcinoma-bearing mice

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