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Upgrading HepG2 cells with adenoviral vectors that encode drug-metabolizing enzymes: application for drug
M José Gómez-Lechón1,2, Laia Tolosa1, M Teresa Donato1,2,3
1a Unidad de Hepatología Experimental , Instituto de Investigación Sanitaria La Fe (IIS La Fe) , Valencia , Spain.
Introduction:
Drug attrition rates due to hepatotoxicity are an important safety issue considered in drug development. The HepG2 hepatoma cell line is currently being used for drug-induced hepatotoxicity evaluations, but its expression of drug-metabolizing enzymes is poor compared with hepatocytes. Different approaches have been proposed to upgrade HepG2 cells for more reliable drug-induced liver injury predictions. Areas covered: We describe the advantages and limitations of HepG2 cells transduced with adenoviral vectors that encode drug-metabolizing enzymes for safety risk assessments of bioactivable compounds. Adenoviral transduction facilitates efficient and controlled delivery of multiple drug-metabolizing activities to HepG2 cells at comparable levels to primary human hepatocytes by generating an 'artificial hepatocyte'. Furthermore, adenoviral transduction enables the design of tailored cells expressing particular metabolic capacities. Expert opinion: Upgraded HepG2 cells that recreate known inter-individual variations in hepatic CYP and conjugating activities due to both genetic (e.g., polymorphisms) or environmental (e.g., induction, inhibition) factors seems a suitable model to identify bioactivable drug and conduct hepatotoxicity risk assessments. This strategy should enable the generation of customized cells by reproducing human pheno- and genotypic CYP variability to represent a valuable human hepatic cell model to develop new safer drugs and to improve existing predictive toxicity assays.
Insights
Upgraded HepG2 cells using adenoviral vectors improve drug-induced liver injury predictions by expressing key drug-metabolizing enzymes. This creates a more reliable model for assessing drug safety and reducing attrition rates in development.
Area of Science:
- Hepatotoxicity and Drug Development
- Cellular Biology and Toxicology
- Pharmacology and Drug Metabolism
Background:
- Drug-induced hepatotoxicity is a major cause of attrition in drug development.
- HepG2 cells have limited drug-metabolizing enzyme expression compared to primary hepatocytes.
- Improved in vitro models are needed for accurate drug-induced liver injury prediction.
Purpose of the Study:
- To evaluate HepG2 cells transduced with adenoviral vectors encoding drug-metabolizing enzymes.
- To assess the utility of these upgraded cells for drug-induced hepatotoxicity risk assessment.
- To explore the potential for creating 'artificial hepatocytes' for drug safety evaluations.
Main Methods:
- Adenoviral transduction of HepG2 cells to express drug-metabolizing enzymes.
- Comparison of enzyme expression levels with primary human hepatocytes.
- Assessment of HepG2 cells for predicting hepatotoxicity of bioactivable compounds.
Main Results:
- Adenoviral transduction efficiently delivers multiple drug-metabolizing activities to HepG2 cells.
- Transduced HepG2 cells achieve enzyme levels comparable to primary human hepatocytes.
- Tailored cell lines expressing specific metabolic capacities can be designed.
Conclusions:
- Upgraded HepG2 cells serve as a suitable model for identifying bioactivable drugs and assessing hepatotoxicity risks.
- These cells can mimic inter-individual variations in hepatic enzyme activity.
- This strategy offers a valuable human hepatic cell model for developing safer drugs and improving toxicity assays.
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