Upgrading HepG2 cells with adenoviral vectors that encode drug-metabolizing enzymes: application for drug hepatotoxicity testing.
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.
a Unidad de Hepatología Experimental , Instituto de Investigación Sanitaria La Fe (IIS La Fe) , Valencia , Spain.|b CIBEREHD, FIS , Spain.
M José
MJ
Gómez-Lechón
a Unidad de Hepatología Experimental , Instituto de Investigación Sanitaria La Fe (IIS La Fe) , Valencia , Spain.
Laia
L
Tolosa
a Unidad de Hepatología Experimental , Instituto de Investigación Sanitaria La Fe (IIS La Fe) , Valencia , Spain.|b CIBEREHD, FIS , Spain.|c Departamento de Bioquímica y Biología Molecular, Facultad de Medicina , Universidad de Valencia , Valencia , Spain.
M Teresa
MT
Donato
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000209:etiology; D015195:Drug Design; D005822:Genetic Vectors / Q000008:administration & dosage; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D004364:Pharmaceutical Preparations / Q000378:metabolism; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods*; D018675:Toxicity Tests / Q000379:methods*
D004364:Pharmaceutical Preparations
CYP; CYP-engineered cell line; HepG2 cells; adenoviral vectors; drug metabolism; hepatotoxicity