Genomic Consequences of Cytochrome P450 2C9 Overexpression in Human Hepatoma Cells - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Chemical Research in Toxicology Année : 2009

Genomic Consequences of Cytochrome P450 2C9 Overexpression in Human Hepatoma Cells

Résumé

Cytochrome P450 2C9 (P450 2C9) is one of the most important P450 isoforms in the human liver, as it metabolizes numerous exogenous and endogenous substrates. Moreover, it is inducible by several compounds, such as rifampicin, phenobarbital, and NSAIDs (nonsteroidal anti-inflammatories). The aim of this study was to investigate the global cellular consequences of P450 2C9 overexpression at the transcriptional level using an untargeted approach: pangenomic microarrays. Recombinant adenovirus was used to express P450 2C9 instead of an inducer to prevent a per se effect of inducer or its metabolites. P450 2C9 overexpression induced endoplasmic reticulum (ER) stress and regulated genes implicated in the unfolded protein response (UPR) as heat shock protein (HSP) (we studied particurlarly HSPA5 and HSPB1) and in the endoplasmic reticulum associated degradation (ERAD) system as Sec61 and ubiquitin and proteasome pathways. UPR and ERAD are two mechanisms of adaptative response to ER stress. Moreover, activation of Akt was observed in HepG2 cells that overexpress P450 2C9 and might participate in the cellular adaptive response to stress, thus leading to the activation of cell survival pathways. UPR and ERAD should be caused by accumulation of native and misfolded P450 2C9 protein. Our results indicated that P450 2C9 overexpression did not lead to toxicity but induced an ER stress due to protein overexpression rather than mono-oxygenase activity. The ER stress triggered activation of the adaptative response and of pathways leading to cell survival.
Fichier principal
Vignette du fichier
49529_20120515100724353_1.pdf (2.37 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Loading...

Dates et versions

hal-02664638 , version 1 (31-05-2020)

Identifiants

Citer

Céline Narjoz, Laetitia Marisa, Sandrine Imbeaud, Alain Paris, Hervé Delacroix, et al.. Genomic Consequences of Cytochrome P450 2C9 Overexpression in Human Hepatoma Cells. Chemical Research in Toxicology, 2009, 22 (5), pp.779-787. ⟨10.1021/tx800417u⟩. ⟨hal-02664638⟩
33 Consultations
155 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More