Lack of inhibitory effect of wood creosote on cytochrome P450‐mediated drug metabolism

Vinpocetine is a derivative of the alkaloid vincamine, which had been prescribed for chronic cerebral vascular ischemia and acute ischemic stroke or used as a dietary supplement for its several different mechanisms of biological activities. However, information on the cytochrome P450 (CYP) enzyme-mediated drug metabolism has not been previously studied. The present study was performed to investigate the effects of vinpocetine on CYPs activity, and cocktail method was used, respectively. To evaluate the effects of vinpocetine on the activity of human CYP3A4, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, human liver microsomes were utilized to incubate with the mixed CYPs probe substrates and the target components. The results indicate that vinpocetine exhibited weak inhibitory effect on the CYP2C9, where the IC50value is 68.96 μM, whereas the IC50values for CYP3A4, CYP2C19, CYP2D6, and CYP2E1 were all over range of 100 μM, which showed that vinpocetine had no apparent inhibitory effects on these CYPs. In conclusion, the results indicated that drugs metabolized by CYP2C9 coadministrated with vinpocetine may require attention or dose adjustment.

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Faculty Opinions recommendation of SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3128957.2811055 ◽

2010 ◽

Author(s):

Gerald Shipps ◽

Xiaohua Huang

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism

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Biology of Heme: Drug Interactions and Adverse Drug Reactions with CYP450

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666181129124638 ◽

2019 ◽

Vol 18 (23) ◽

pp. 2042-2055 ◽

Cited By ~ 4

Author(s):

Neeraj Kumar ◽

Heerak Chugh ◽

Damini Sood ◽

Snigdha Singh ◽

Aarushi Singh ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Drug Interactions ◽

Adverse Drug Reactions ◽

Genetic Defects ◽

Drug Reactions ◽

Detailed Structure ◽

Synthesis And Degradation ◽

Porphyrin Rings

Heme is central to functions of many biologically important enzymes (hemoproteins). It is an assembly of four porphyrin rings joined through methylene bridges with a central Fe (II). Heme is present in all cells, and its synthesis and degradation balance its amount in the cell. The deregulations of heme networks and incorporation in hemoproteins lead to pathogenic state. This article addresses the detailed structure, biosynthesis, degradation, and transportation associated afflictions to heme. The article is followed by its roles in various diseased conditions where it is produced mainly as the cause of increased hemolysis. It manifests the symptoms in diseases as it is a pro-oxidant, pro-inflammatory and pro-hemolytic agent. We have also discussed the genetic defects that tampered with the biosynthesis, degradation, and transportation of heme. In addition, a brief about the largest hemoprotein group of enzymes- Cytochrome P450 (CYP450) has been discussed with its roles in drug metabolism.

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Roles of Human Cytochrome P450 Enzymes Involved in Drug Metabolism and Toxicological Studies

YAKUGAKU ZASSHI ◽

10.1248/yakushi1947.120.12_1347 ◽

2000 ◽

Vol 120 (12) ◽

pp. 1347-1357 ◽

Cited By ~ 4

Author(s):

Hiroshi YAMAZAKI

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Cytochrome P450 Enzymes ◽

Human Cytochrome ◽

Toxicological Studies

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Anti‐interleukin‐6 antibody clazakizumab in late antibody‐mediated kidney transplant rejection: effect on cytochrome P450 drug metabolism

Transplant International ◽

10.1111/tri.13954 ◽

2021 ◽

Author(s):

Jakob Mühlbacher ◽

Christian Schörgenhofer ◽

Konstantin Doberer ◽

Michael Dürr ◽

Klemens Budde ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Kidney Transplant ◽

Interleukin 6 ◽

Transplant Rejection

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Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

Archives of Toxicology ◽

10.1007/s00204-021-03075-3 ◽

2021 ◽

Author(s):

Lawrence Howell ◽

Rosalind E. Jenkins ◽

Stephen Lynch ◽

Carrie Duckworth ◽

B. Kevin Park ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Rna Polymerase Ii ◽

Liver Tissue ◽

Drug Disposition ◽

Multiple Drug ◽

Proteomic Profiling ◽

Cytochrome P450 3A ◽

Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

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In vitro study on the effect of cornin on the activity of cytochrome P450 enzymes

BMC Complementary Medicine and Therapies ◽

10.1186/s12906-021-03309-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Qun Zhang ◽

Zengqiang Qu ◽

Yanqing Zhou ◽

Jin Zhou ◽

Junwei Yang ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Liver Microsomes ◽

In Vitro Study ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cytochrome P450 Enzymes ◽

Drug Drug Interaction ◽

Dose Dependent

Abstract Background Cornin is a commonly used herb in cardiology for its cardioprotective effect. The effect of herbs on the activity of cytochrome P450 enzymes (CYP450s) can induce adverse drug-drug interaction even treatment failure. Therefore, it is necessary to investigate the effect of cornin on the activity of CYP450s, which can provide more guidance for the clinical application of cornin. Methods Cornin (100 μM) was incubated with eight isoforms of CYP450s, including CYP1A2, 2A6, 3A4, 2C8, 2C9, 2C19, 2D6, and 2E1, in pooled human liver microsomes. The inhibition model and corresponding parameters were also investigated. Results Cornin exerted significant inhibitory effect on the activity of CYP3A4, 2C9, and 2E1 in a dose-dependent manner with the IC50 values of 9.20, 22.91, and 14.28 μM, respectively (p < 0.05). Cornin inhibited the activity of CYP3A4 non-competitively with the Ki value of 4.69 μM, while the inhibition of CYP2C9 and 2E1 by cornin was competitive with the Ki value of 11.31 and 6.54 μM, respectively. Additionally, the inhibition of CYP3A4 by cornin was found to be time-dependent with the KI/Kinact value of 6.40/0.055 min− 1·μM− 1. Conclusions The inhibitory effect of cornin on the activity of CYP3A4, 2C9, and 2E1 indicated the potential drug-drug interaction between cornin and drugs metabolized by these CYP450s, which needs further investigation and validation.

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