scholarly journals Cryopreserved Human Intestinal Mucosal Epithelium: A Novel In Vitro Experimental System for the Evaluation of Enteric Drug Metabolism, Cytochrome P450 Induction, and Enterotoxicity

2018 ◽  
Vol 46 (11) ◽  
pp. 1562-1571 ◽  
Author(s):  
Albert P. Li ◽  
Novera Alam ◽  
Kirsten Amaral ◽  
Ming-Chih David Ho ◽  
Carol Loretz ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Experimental System ◽  
Mucosal Epithelium ◽  
Cytochrome P450 Induction

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.

scholarly journals Sequencing of the Canine Cytochrome P450 CYP2C41 Gene and Genotyping of Its Polymorphic Occurrence in 36 Dog Breeds

2021 ◽  
Vol 8 ◽  
Author(s):  
Emre Karakus ◽  
Clarissa Prinzinger ◽  
Silke Leiting ◽  
Joachim Geyer
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Gene Deletion ◽  
Homologous Sequence ◽  
Pharmacokinetic Studies ◽  
Metabolizing Enzymes ◽  
Genomic Level ◽  
Very High

Cytochrome P450 (CYP) drug metabolizing enzymes play an important role in efficient drug metabolism and elimination. Many CYPs are polymorphic and, thereby, drug metabolism can vary between individuals. In the case of canine CYP2C41, gene polymorphism was identified. However, as the first available canine genome sequences all were CYP2C41 negative, this polymorphism could not be clarified at the genomic level. The present study provides an exact characterization of the CYP2C41 gene deletion polymorphism at the genomic level and presents a PCR-based genotyping method that was used for CYP2C41 genotyping of 1,089 individual subjects from 36 different dog breeds. None of the Bearded Collie, Bernese Mountain, Boxer, Briard, French Bulldog or Irish Wolfhound subjects had the CYP2C41 gene in their genomes. In contrast, in the Chinese Char-Pei, Siberian Husky, Schapendoes and Kangal breeds, the CYP2C41 allele frequency was very high, with values of 67, 57, 43, and 34%, respectively. Interestingly, the site of gene deletion was identical for all CYP2C41 negative dogs, and all CYP2C41 positive dogs showed highly homologous sequence domains upstream and downstream from the CYP2C41 gene. CYP2C41 genotyping can now be routinely used in future pharmacokinetic studies in canines, in order to identify genetically-based poor or extensive drug metabolizers. This, together with more extensive in vitro drug screening for CYP2C41 substrates will help to determine the clinical relevance of CYP2C41, and to optimize drug treatment. Although the relative abundance of the CYP2C41 protein in the canine liver seems to not be very high, this CYP could substantially contribute to hepatic drug metabolism in dogs expressing CYP2C41 from both alleles and, when CYP2C41 shows higher catalytic activity to a given drug than other hepatic metabolic enzymes.

Nitric Oxide Mediates Hepatic Cytochrome P450 Dysfunction Induced by Endotoxin

1996 ◽  
Vol 84 (6) ◽  
pp. 1435-1442 ◽  
Author(s):  
Claudia M. Muller ◽  
Annette Scierka ◽  
Richard L. Stiller ◽  
Yong-Myeong Kim ◽  
Ryan D. Cook ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Sprague Dawley ◽  
Cytochrome P450 Content ◽  
Nitrate Concentrations ◽  
Hypnotic Drugs ◽  
Plasma Nitrite

Background Animals subjected to immunostimulatory conditions (sepsis) exhibit decreased total cytochrome P450 content and decreased P450-dependent drug metabolism. Cytochrome P450 function is of clinical significance because it mediates the metabolism of some opioid and hypnotic drugs. The authors tested the hypothesis that reduced P450 function and decreased drug metabolism in sepsis are mediated by endotoxin-enhanced synthesis of nitric oxide. Methods Hepatic microsomes were prepared from male Sprague-Dawley rats in nontreated rats, rats pretreated with phenobarbital and rats receiving aminoguanidine or NG-L-monomethyl-arginine alone. Nitric oxide synthesis was augmented for 12 h with a single injection of bacterial lipopolysaccharides. Nitric oxide synthase was inhibited with aminoguanidine or N(G)-L-monomethyl-arginine during the 12 h of endotoxemia in some animals. Plasma nitrite and nitrate concentrations were measured in vivo, and total microsomal P450 content, and metabolism of ethylmorphine and midazolam in vitro. Results Administration of endotoxin increased plasma nitrite and nitrate concentrations, decreased total cytochrome P450 content, and decreased metabolism of ethylmorphine and midazolam. Inhibition of nitric oxide formation by aminoguanidine or N(G)-L-monomethyl-arginine partially prevented the endotoxin-induced effects in the nontreated and phenobarbital-treated groups. Aminoguanidine or N(G)-L-monomethyl-arginine alone did not have an effect on either total cytochrome P450 content or P450-dependent drug metabolism. Plasma nitrite and nitrate concentrations correlated significantly negatively with P450 content (nontreated r = -0.88, phenobarbital r = -0.91), concentrations of formed formaldehyde (nontreated r = -0.87, phenobarbital r = -0.95), and concentrations of midazolam metabolites (4-OH midazolam nontreated r = -0.88, phenobarbital r = -0.93, and 1'-OH midazolam nontreated r = -0.88, phenobarbital r = -0.97). Conclusions Altered hepatic microsomal ethylmorphine and midazolam metabolism during sepsis is mediated in large part by nitric oxide.

HepG2 cells as an in vitro model for evaluation of cytochrome P450 induction by xenobiotics

2014 ◽  
Vol 38 (5) ◽  
pp. 691-704 ◽  
Author(s):  
Jong Min Choi ◽  
Soo Jin Oh ◽  
Sang Yoon Lee ◽  
Ji Hye Im ◽  
Jung Min Oh ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Hepg2 Cells ◽  
In Vitro Model ◽  
Cytochrome P450 Induction ◽  
Vitro Model

scholarly journals Effects of Ospemifene on Drug Metabolism Mediated by Cytochrome P450 Enzymes in Humans in Vitro and in Vivo

2013 ◽  
Vol 14 (7) ◽  
pp. 14064-14075 ◽  
Author(s):  
Miia Turpeinen ◽  
Jouko Uusitalo ◽  
Terhi Lehtinen ◽  
Marita Kailajärvi ◽  
Olavi Pelkonen ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Drug Metabolism ◽  
Cytochrome P450 Enzymes

Comparison of Immortalized Fa2N-4 Cells and Human Hepatocytes as in Vitro Models for Cytochrome P450 Induction

2008 ◽  
Vol 36 (6) ◽  
pp. 1046-1055 ◽  
Author(s):  
Niresh Hariparsad ◽  
Brian A. Carr ◽  
Raymond Evers ◽  
Xiaoyan Chu
Keyword(s):  
Cytochrome P450 ◽  
In Vitro Models ◽  
Human Hepatocytes ◽  
Cytochrome P450 Induction

In vitro evaluation of cytochrome P450 induction and the inhibition potential of mitragynine, a stimulant alkaloid

2013 ◽  
Vol 27 (2) ◽  
pp. 812-824 ◽  
Author(s):  
Ee Lin Lim ◽  
Tiong Chai Seah ◽  
Xue Fen Koe ◽  
Habibah Abdul Wahab ◽  
Mohd Ilham Adenan ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Vitro Evaluation ◽  
Cytochrome P450 Induction

Utility of Long-Term Cultured Human Hepatocytes as an in Vitro Model for Cytochrome P450 Induction

2006 ◽  
Vol 35 (2) ◽  
pp. 215-220 ◽  
Author(s):  
Georgina Meneses-Lorente ◽  
Christine Pattison ◽  
Claire Guyomard ◽  
Christophe Chesné ◽  
Robert Heavens ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
In Vitro Model ◽  
Human Hepatocytes ◽  
Cytochrome P450 Induction ◽  
Vitro Model
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