Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity

Epigenetic Modifications of the Liver Tumor Cell Line HepG2 Increase Their Drug Metabolic Capacity

Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizin...

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Bibliographic Details
Published in:International journal of molecular sciences Vol. 20; no. 2; p. 347
Main Authors: Ruoß, Marc, Damm, Georg, Vosough, Massoud, Ehret, Lisa, Grom-Baumgarten, Carl, Petkov, Martin, Naddalin, Silvio, Ladurner, Ruth, Seehofer, Daniel, Nussler, Andreas, Sajadian, Sahar
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 16-01-2019
MDPI
Subjects:
Albumins
Biotechnology
Cell culture
Chromatin
Culture media
DNA methylation
drug metabolism
Enzymes
epigenetic reprogramming
Epigenetics
Gene expression
Glucocorticoids
Hepatocytes
Hepatoma
hepatoma cell lines
Hydrocortisone
Insulin
Investigations
Liver
Liver cancer
Maintenance
Metabolism
Preservation
primary human hepatocytes
Tumor cell lines
Tumor cells
Tumors
Vitamin C
epigenetic reprogramming
hepatoma cell lines
tumor cells
primary human hepatocytes
drug metabolism
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Summary:Although human liver tumor cells have reduced metabolic functions as compared to primary human hepatocytes (PHH) they are widely used for pre-screening tests of drug metabolism and toxicity. The aim of the present study was to modify liver cancer cell lines in order to improve their drug-metabolizing activities towards PHH. It is well-known that epigenetics is strongly modified in tumor cells and that epigenetic regulators influence the expression and function of Cytochrome P450 (CYP) enzymes through altering crucial transcription factors responsible for drug-metabolizing enzymes. Therefore, we screened the epigenetic status of four different liver cancer cell lines (Huh7, HLE, HepG2 and AKN-1) which were reported to have metabolizing drug activities. Our results showed that HepG2 cells demonstrated the highest similarity compared to PHH. Thus, we modified the epigenetic status of HepG2 cells towards 'normal' liver cells by 5-Azacytidine (5-AZA) and Vitamin C exposure. Then, mRNA expression of Epithelial-mesenchymal transition (EMT) marker SNAIL and CYP enzymes were measured by PCR and determinate specific drug metabolites, associated with CYP enzymes by LC/MS. Our results demonstrated an epigenetic shift in HepG2 cells towards PHH after exposure to 5-AZA and Vitamin C which resulted in a higher expression and activity of specific drug metabolizing CYP enzymes. Finally, we observed that 5-AZA and Vitamin C led to an increased expression of Hepatocyte nuclear factor 4α (HNF4α) and E-Cadherin and a significant down regulation of Snail1 (SNAIL), the key transcriptional repressor of E-Cadherin. Our study shows, that certain phase I genes and their enzyme activities are increased by epigenetic modification in HepG2 cells with a concomitant reduction of EMT marker gene SNAIL. The enhancing of liver specific functions in hepatoma cells using epigenetic modifiers opens new opportunities for the usage of cell lines as a potential liver in vitro model for drug testing and development.
Bibliography:These authors contributed equally to this work.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms20020347