Maintenance of liver function in long term culture of hepatocytes following In Vitro or In Vivo Ha-ras EJ transfection

Fischbach, Michel; Cao, Hanwei; Ibáñez, Miguel; Tsaconas, Christos; Alouani, Sami; Montandon, Frédéric; Baraka, Mohammed El; Padieu, P; Dréano, Michel; Chessebeuf-Padieu, Martine

doi:10.1007/bf00124069

Cited by 11 publications

(3 citation statements)

References 56 publications

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“…BROD activity, and in part PROD, is specific of CYP2B6. simian virus 40 large T antigen, c-myc, cHras) [37][38][39], the generation of cell lines from transgenic animals expressing viral transforming genes, oncogenes or growth factors [40,41], or hydrid cells obtained by the fusion of hepatocytes and immortalized cell lines [42,43]. CLZX and pNPH are catalyzed by CYP2E1, and DOH and T6 OH are indicative of CYP2C9 and CYP3A4, respectively.…”

Section: Human Liver-derived Cell Linesmentioning

confidence: 99%

Cell Lines: A Tool for In Vitro Drug Metabolism Studies

Donato

Lahoz²,

Castell³

et al. 2008

CDM

258

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Primary cultured hepatocytes are a valuable in vitro model for drug metabolism studies. However, their widespread use is greatly hindered by the scarcity of suitable human liver samples. Moreover, the well-known in vitro phenotypic instability of hepatocytes, the irregular availability of fresh human liver for cell harvesting purposes, and the high batch-to-batch functional variability of hepatocyte preparations obtained from different human liver donors, seriously complicate their use in routine testing. To overcome these limitations, different cell line models have been proposed for drug metabolism screening. Human liver-derived cell lines would be ideal models for this purpose given their availability, unlimited life-span, stable phenotype, and the fact that they are easy to handle. However, the human hepatoma cells currently used (i.e. HepG2, Mz-Hep-1) show negligible levels of drug-metabolizing and do not constitute a real alternative to primary hepatocytes. Different strategies have been proposed to generate metabolically competent immortalized hepatocytes (transformation of human hepatocytes with plasmids encoding immortalizing genes, hepatocyte-like cells derived from stem cells, cell lines generated from transgenic animals, hepatocyte/hepatoma hydrid cells). Moreover, recombinant models heterologously expressing P450 enzymes in different host cells have been developed and successfully used in drug metabolism testing. In addition, new strategies have recently been explored to upregulate the expression of drug-metabolizing enzymes in cell lines of a human origin (i.e. transfection with expression vectors encoding key hepatic transcription factors). Among metabolic-based drug-drug interactions, P450 inhibition seems to be the most important. A major application of recombinant models expressing a single P450 is the screening of potential enzyme inhibitors. Therefore, pharmaceutical companies increasingly make use of cell lines to speed up the selection of new drugs with favourable pharmacokinetic and metabolic properties.

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Section: Human Liver-derived Cell Linesmentioning

confidence: 99%

Cell Lines: A Tool for In Vitro Drug Metabolism Studies

Donato

Lahoz²,

Castell³

et al. 2008

CDM

258

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“…Ultimately, our aim is to transfect human hepatocytes and some progress in this direction has been made in the production of immortalised chimpanzee hepatocytes,3~ and human embryonic and foetal liver derived epithelial cells. 18,19 However, the limited availability of human tissue and the difficulties in isolating human cell lines which are genuinely immortal make it likely that rodent lines will be an important resource in toxicological studies for some time to come.…”

Section: Resultsmentioning

confidence: 99%

Expression of Liver Functions in Imrnortalised Rot Hepotocyte Cell Lines

et al. 1994

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The differentiated hepatic function of two rat liver cell lines, P9 and SV40RH1, immortalised by transfection with SV40 DNA has been investigated in terms of the glutathione synthesis, and the activities of γ-glutamyltransferase, glutathione-S-transferase and UDP-glucuronosyltransferase. SV40RH1 is a highly differentiated cell line at early passage, but the expression of some aspects of its differentiated phenotype is unstable and some functions are lost by passage 12-13. P9 is a less-well differentiated cell line, with relatively stable expression of functions between passages 4 and 13. In terms of differentiated function both cell lines represent a marked improvement over primary cultures of rat hepatocytes which de-differentiate rapidly within 24-48 h in culture. This retention of liver function in proliferating cell lines offers the opportunity to use such cells in in vitro toxicological studies.

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“…Several factors are involved in the repression of CYP genes in hepatic cells [ 29 , 30 ]. Oncogenes (Ha-rasEJ, met, c-Ha-ras) have been reported to be effective in transforming hepatocytes [ 31 - 33 ]. The resulting transformed hepatocytes expressed low levels of drug metabolizing activities [ 34 ].…”

Section: Hepatic Cell Lines Models For Evaluation Of Drug-induced LIVmentioning

confidence: 99%

Models of Drug Induced Liver Injury (DILI) – Current Issues and Future Perspectives

Kuna

Božić

Kizivat

et al. 2018

CDM

102

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Background: Drug-induced Liver Injury (DILI) is an important cause of acute liver failure cases in the United States, and remains a common cause of withdrawal of drugs in both preclinical and clinical phases.Methods: A structured search of bibliographic databases – Web of Science Core Collection, Scopus and Medline for peer-reviewed articles on models of DILI was performed. The reference lists of relevant studies was prepared and a citation search for the included studies was carried out. In addition, the characteristics of screened studies were described.Results: One hundred and six articles about the existing knowledge of appropriate models to study DILI in vitro and in vivo with special focus on hepatic cell models, variations of 3D co-cultures, animal models, databases and predictive modeling and translational biomarkers developed to understand the mechanisms and pathophysiology of DILI are described.Conclusion: Besides descriptions of current applications of existing modeling systems, associated advantages and limitations of each modeling system and future directions for research development are discussed as well.

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Maintenance of liver function in long term culture of hepatocytes following In Vitro or In Vivo Ha-ras EJ transfection

Cited by 11 publications

References 56 publications

Cell Lines: A Tool for In Vitro Drug Metabolism Studies

Cell Lines: A Tool for In Vitro Drug Metabolism Studies

Expression of Liver Functions in Imrnortalised Rot Hepotocyte Cell Lines

Models of Drug Induced Liver Injury (DILI) – Current Issues and Future Perspectives

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