Cytochrome P450 3A-Dependent Metabolism of a Potent and Selective γ-Aminobutyric AcidAα2/3 Receptor Agonist in Vitro: Involvement of Cytochrome P450 3A5 Displaying Biphasic Kinetics

2007 ◽  
Vol 35 (8) ◽  
pp. 1301-1307 ◽  
Author(s):  
Bennett Ma ◽  
Stacey L. Polsky-Fisher ◽  
Stanley Vickers ◽  
Donghui Cui ◽  
A. David Rodrigues
Keyword(s):  
Cytochrome P450 ◽  
Receptor Agonist ◽  
Cytochrome P450 3A ◽  
Biphasic Kinetics ◽  
Cytochrome P450 3A5

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

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.

Does Crizotinib Auto-Inhibit CYP3A in vivo?

Pharmacology ◽  
2020 ◽  
Vol 105 (11-12) ◽  
pp. 715-718
Author(s):  
Abigail R. Bland ◽  
Nensi Shrestha ◽  
Rhonda J. Rosengren ◽  
John C. Ashton
Keyword(s):  
Lung Cancer ◽  
Cytochrome P450 ◽  
Western Blot ◽  
Anaplastic Lymphoma Kinase ◽  
Kinase Inhibitor ◽  
Cyp3a Activity ◽  
Cytochrome P450 3A ◽  
Anaplastic Lymphoma

Crizotinib is a tyrosine kinase inhibitor used to treat anaplastic lymphoma kinase-positive lung cancer. There is in vitro evidence that crizotinib may auto-inhibit cytochrome P450 3A (CYP3A) activity, with important implications for crizotinib pharmacokinetics. In order to test whether crizotinib treatment alters CYP3A activity in vivo, mice were treated with 5 and 25 mg/kg crizotinib (p.o.) daily for 14 days. Results showed that crizotinib treatment did not alter CYP3A activity as determined by erythromycin <i>N</i>-demethylation. In addition, CYP3A polypeptide expression as measured by Western blot was unchanged. Therefore, our results do not support CYP3A inhibition by crizotinib in vivo.

scholarly journals Inhibitory Effect of Lygodium Root on the Cytochrome P450 3A Enzyme in vitro and in vivo

2020 ◽  
Vol Volume 14 ◽  
pp. 1909-1919
Author(s):  
Yunfang Zhou ◽  
Ailian Hua ◽  
Quan Zhou ◽  
Peiwu Geng ◽  
Feifei Chen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Inhibitory Effect ◽  
Cytochrome P450 3A

scholarly journals In vitro and in vivo cytochrome P450 3A enzyme inhibition by Aframomum melegueta and Denniettia tripetala extracts

2017 ◽  
Vol 10 (6) ◽  
pp. 576-581 ◽  
Author(s):  
Sunday O. Nduka ◽  
Mathew J. Okonta ◽  
Daniel L. Ajaghaku ◽  
Chinwe V. Ukwe
Keyword(s):  
Cytochrome P450 ◽  
Enzyme Inhibition ◽  
Cytochrome P450 3A

Developmental Changes in the Expression and Function of Cytochrome P450 3A Isoforms: Evidence from In Vitro and In Vivo Investigations

2013 ◽  
Vol 52 (5) ◽  
pp. 333-345 ◽  
Author(s):  
Ibrahim Ince ◽  
Catherijne A. J. Knibbe ◽  
Meindert Danhof ◽  
Saskia N. de Wildt
Keyword(s):  
Cytochrome P450 ◽  
Developmental Changes ◽  
Cytochrome P450 3A ◽  
And Function

scholarly journals Effects of resveratrol on P-glycoprotein and cytochrome P450 3A in vitro and on pharmacokinetics of oral saquinavir in rats

2016 ◽  
Vol Volume 10 ◽  
pp. 3699-3706 ◽  
Author(s):  
Jiapeng Li ◽  
Yang Liu ◽  
Jingru Zhang ◽  
Xiaotong Yu ◽  
Xiaoling Wang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 3A ◽  
P Glycoprotein
Sign in / Sign up

Export Citation Format

Share Document