Advanced Approaches to Model Xenobiotic Metabolism in Bacterial Genotoxicology In Vitro

2016 ◽  
pp. 97-134
Author(s):  
Yoshimitsu Oda
Keyword(s):  
Xenobiotic Metabolism

scholarly journals Xenobiotica-metabolizing enzymes in the lung of experimental animals, man and in human lung models

2019 ◽  
Vol 93 (12) ◽  
pp. 3419-3489 ◽  
Author(s):  
F. Oesch ◽  
E. Fabian ◽  
Robert Landsiedel
Keyword(s):  
Human Lung ◽  
Cytochromes P450 ◽  
Xenobiotic Metabolism ◽  
In Vitro Models ◽  
Work Place ◽  
Individual Species ◽  
Alveolar Type ◽  
Vitro Model ◽  
Few Data

Abstract The xenobiotic metabolism in the lung, an organ of first entry of xenobiotics into the organism, is crucial for inhaled compounds entering this organ intentionally (e.g. drugs) and unintentionally (e.g. work place and environmental compounds). Additionally, local metabolism by enzymes preferentially or exclusively occurring in the lung is important for favorable or toxic effects of xenobiotics entering the organism also by routes other than by inhalation. The data collected in this review show that generally activities of cytochromes P450 are low in the lung of all investigated species and in vitro models. Other oxidoreductases may turn out to be more important, but are largely not investigated. Phase II enzymes are generally much higher with the exception of UGT glucuronosyltransferases which are generally very low. Insofar as data are available the xenobiotic metabolism in the lung of monkeys comes closed to that in the human lung; however, very few data are available for this comparison. Second best rate the mouse and rat lung, followed by the rabbit. Of the human in vitro model primary cells in culture, such as alveolar macrophages and alveolar type II cells as well as the A549 cell line appear quite acceptable. However, (1) this generalization represents a temporary oversimplification born from the lack of more comparable data; (2) the relative suitability of individual species/models is different for different enzymes; (3) when more data become available, the conclusions derived from these comparisons quite possibly may change.

scholarly journals Changes in cytochrome P450 gene expression and enzyme activity induced by xenobiotics in rabbits in vivo and in vitro

2017 ◽  
Vol 25 (2) ◽  
pp. 173 ◽  
Author(s):  
Orsolya Palócz ◽  
Orsolya Farkas ◽  
Paul Clayton ◽  
György Csikó
Keyword(s):  
Gene Expression ◽  
Cytochrome P450 ◽  
Toxicity Testing ◽  
Xenobiotic Metabolism ◽  
Cytochrome P450 Enzyme ◽  
Primary Hepatocytes ◽  
Short Term ◽  
P450 Gene

As considerable inter-species differences exist in xenobiotic metabolism, developing new pharmaceutical therapies for use in different species is fraught with difficulties. For this reason, very few medicines have been registered for use in rabbits, despite their importance in inter alia meat and fur production. We have developed a rapid and sensitive screening system for drug safety in rabbits based on cytochrome P450 enzyme assays, specifically CYP1A1, CYP1A2 and CYP3A6, employing an adaptation of the luciferin-based clinical assay currently used in human drug screening. Short-term (4-h) cultured rabbit primary hepatocytes were treated with a cytochrome inducer (phenobarbital) and 2 inhibitors (alpha-naphthoflavone and ketoconazole). In parallel, and to provide verification, New Zealand white rabbits were dosed with 80 mg/kg phenobarbital or 40 mg/kg ketoconazole for 3 d. Ketoconazole significantly increased CYP3A6 gene expression and decreased CYP3A6 activity both in vitro and in vivo. CYP1A1 activity was decreased by ketoconazole in vitro and increased in vivo. This is the first report of the inducer effect of ketoconazole on rabbit cytochrome isoenzymes in vivo. Our data support the use of a luciferin-based assay in short-term primary hepatocytes as an appropriate tool for xenobiotic metabolism assays and short-term toxicity testing in rabbits.<p> </p>

In Vitro Xenobiotic metabolism by sea anemone microsomes

1998 ◽  
Vol 46 (1-5) ◽  
pp. 534-535
Author(s):  
L.M. Heffernan ◽  
M.H. Mayeaux ◽  
M. Vasquez ◽  
G.W. Winston
Keyword(s):  
Xenobiotic Metabolism ◽  
Sea Anemone

Advanced In Vitro HepaRG Culture Systems for Xenobiotic Metabolism and Toxicity Characterization

2018 ◽  
Vol 44 (4) ◽  
pp. 437-458 ◽  
Author(s):  
Muhammad Nadeem Ashraf ◽  
Muhammad Waheed Asghar ◽  
Yan Rong ◽  
Michael R. Doschak ◽  
Tony K. L. Kiang
Keyword(s):  
Xenobiotic Metabolism ◽  
Culture Systems

scholarly journals A Comparative Study of Human and Zebrafish Pregnane X Receptor Activities of Pesticides and Steroids Using In Vitro Reporter Gene Assays

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicolas Creusot ◽  
Clémentine Garoche ◽  
Marina Grimaldi ◽  
Abdelhay Boulahtouf ◽  
Barbara Chiavarina ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nuclear Receptor ◽  
Pregnane X Receptor ◽  
Xenobiotic Metabolism ◽  
Aquatic Species ◽  
Reporter Cell ◽  
Cellular Models ◽  
Potential Risks ◽  
Antagonist Effect

The nuclear receptor pregnane X receptor (PXR) is a ligand-dependent transcription factor that regulates genes involved in xenobiotic metabolism in mammals. Many studies suggest that PXR may play a similar role in fish. The interaction of human PXR (hPXR) with a variety of structurally diverse endogenous and exogenous chemicals is well described. In contrast, little is known about the zebrafish PXR (zfPXR). In order to compare the effects of these chemicals on the PXR of these two species, we established reporter cell lines expressing either hPXR or zfPXR. Using these cellular models, we tested the hPXR and zfPXR activity of various steroids and pesticides. We provide evidence that steroids were generally stronger activators of zfPXR while pesticides were more potent on hPXR. In addition, some chemicals (econazole nitrate, mifepristone, cypermethrin) showed an antagonist effect on zfPXR, whereas no antagonist chemical has been identified for hPXR. These results confirm significant differences in the ability of chemicals to modulate zfPXR in comparison to hPXR and point out that zfPXR assays should be used instead of hPXR assays for evaluating the potential risks of chemicals on aquatic species.

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