Application of In Vitro Metabolism Activation in High-Throughput Screening
Abstract
:1. Introduction
1.1. Phase I and Phase II Metabolism
1.2. Drug Metabolism and Drug-Drug Interactions
1.3. Role of Transcription Factors in CYP450 Regulation
2. In Vitro Metabolism Methods
2.1. Liver S9 Fractions
2.2. Liver Microsomal Fractions
2.3. Liver Cytosolic Fractions
2.4. Hepatocytes
2.5. Hepatoma Cell Lines and Terminally Differentiated HepaRG Cells
2.6. Recombinant Enzymes of Phase I and II Drug Metabolism
2.7. Liver Slices
2.8. Monolayer 2D vs. Spheroid 3D Models
3. Applying In Vitro Metabolism Methods to Quantitative High-Throughput Screening
3.1. Genotoxicity
3.2. Neurotoxicity and Developmental Neurotoxicity
3.3. Hepatotoxicity
4. Future Perspective
Author Contributions
Funding
Disclaimer
Conflicts of Interest
Abbreviations
AChE | Acetylcholinesterase |
AhR | Aryl hydrocarbon receptor |
CAR | Constitutive androstane receptor |
CYP | Cytochrome p450 |
DDI | Drug–drug interaction |
DME | Drug-metabolizing enzyme |
NR | Nuclear receptor |
OOTC | Organ-on-a-chip |
PXR | Pregnane X receptor |
qHTS | Quantitative high-throughput screening |
UGT | Glucuronosyltransferase |
2D | Two dimensional |
3D | Three dimensional |
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Metabolic Components/Cells [References] | Pros | Cons |
---|---|---|
Recombinant protein [36] | Single metabolizing protein focus HTS compatible | Missing cellular component |
Liver microsomes [37,38] | Less cytotoxicity Major phase I enzymes such as CYPs Commercially available Short protocol HTS compatible | Less phase II enzymes such as SULT |
Liver cytosol [38] | Major phase II enzymes such as GST Commercially available | No CYPs |
Liver S9 fractions [38] | Physiological phase I and II enzymes Commercially available Short protocol | High cytotoxicity |
Hepatoma cell lines (HepG2, HLE, THLE-2, and Fa2N4) [39,40,41,42,43,44] | Commercially available Well-developed protocols HTS compatible | Less metabolic activity |
3D cell culture [45,46] | Higher metabolic activity | Time consuming Expensive |
Terminally differentiated HepaRG cells [47,48,49,50] | Commercially available Higher metabolic activity | Expensive |
Hepatocytes, liver slices [51,52,53,54,55,56,57] | Commercially available Well-developed protocol All metabolizing enzymes | Lot-to-lot variation Time consuming Expensive |
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Ooka, M.; Lynch, C.; Xia, M. Application of In Vitro Metabolism Activation in High-Throughput Screening. Int. J. Mol. Sci. 2020, 21, 8182. https://doi.org/10.3390/ijms21218182
Ooka M, Lynch C, Xia M. Application of In Vitro Metabolism Activation in High-Throughput Screening. International Journal of Molecular Sciences. 2020; 21(21):8182. https://doi.org/10.3390/ijms21218182
Chicago/Turabian StyleOoka, Masato, Caitlin Lynch, and Menghang Xia. 2020. "Application of In Vitro Metabolism Activation in High-Throughput Screening" International Journal of Molecular Sciences 21, no. 21: 8182. https://doi.org/10.3390/ijms21218182