Document Detail


Drug-metabolising enzymes are down-regulated by hypoxia in differentiated human hepatoma HepaRG cells: HIF-1alpha involvement in CYP3A4 repression.
MedLine Citation:
PMID:  19695866     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Weak blood irrigation within solid tumours including hepatocellular carcinomas (HCCs) plays an important role in resistance to anticancer drugs by decreasing accessibility of cytotoxic agents to tumour cells. Reduced oxygen levels, or hypoxia, also contribute to drug resistance because many anticancer drugs require molecular oxygen to be cytotoxic. Our aim was to develop a new in vitro model mimicking hypoxic cells within HCCs in order to further explore the molecular responses to hypoxia, including regulation of drug-metabolising enzymes (DMEs) expression. For this purpose, we used the highly differentiated human hepatoma HepaRG cells cultured under either normoxic or hypoxic (24h at 1% O(2)) conditions. Gene and protein expressions were investigated by quantitative PCR and immunoblotting, respectively. We showed that HepaRG cells adapt to prolonged moderate hypoxia by a switch from aerobic to anaerobic glycolysis and a repression of critical genes involved in amino acid, lipid and ethanol metabolisms. Importantly, expression of several DMEs (particularly cytochromes P450 (CYPs) and phase II enzymes) and xenosensors (CAR, PXR and AhR) was down-regulated and CYPs activities (using testosterone and paclitaxel as substrates) were decreased during hypoxia. In addition, a new role for HIF-1alpha in the repression of CYP3A4 is demonstrated in cells treated with chemical inducers of HIF-1alpha, cobalt chloride or desferrioxamine, and by transfecting untreated HepaRG cells with HIF-1alpha expression vector. In conclusion, HepaRG cells cultured under hypoxia might mimic metabolic changes occurring within poorly irrigated differentiated HCCs. Furthermore, hypoxia down-regulates hepatic DMEs, a phenomenon that might compromise chemotherapy effectiveness in HCC treatment. Thus, HepaRG cells might represent a new in vitro model to test anticancer agents in hypoxic versus normoxic conditions.
Authors:
Claire Legendre; Tamaki Hori; Pascal Loyer; Caroline Aninat; Seiichi Ishida; Denise Glaise; Catherine Lucas-Clerc; Karim Boudjema; Christiane Guguen-Guillouzo; Anne Corlu; Fabrice Morel
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-18
Journal Detail:
Title:  European journal of cancer (Oxford, England : 1990)     Volume:  45     ISSN:  1879-0852     ISO Abbreviation:  Eur. J. Cancer     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-26     Completed Date:  2010-02-04     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9005373     Medline TA:  Eur J Cancer     Country:  England    
Other Details:
Languages:  eng     Pagination:  2882-92     Citation Subset:  IM    
Affiliation:
INSERM U522, H??pital Pontchaillou, Rennes F-35033, France.
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MeSH Terms
Descriptor/Qualifier:
Antimetabolites
Carcinoma, Hepatocellular / enzymology*
Cell Differentiation
Cell Hypoxia / physiology
Cell Line, Tumor
Cell Survival
Cytochrome P-450 CYP3A / metabolism*
Down-Regulation
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
Liver Neoplasms / enzymology*
Chemical
Reg. No./Substance:
0/Antimetabolites; 0/Hypoxia-Inducible Factor 1, alpha Subunit; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A

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