Involvement of pregnane X receptor in the regulation of CYP2B6 gene expression by oltipraz in human hepatocytes. - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Toxicology in Vitro Année : 2010

Involvement of pregnane X receptor in the regulation of CYP2B6 gene expression by oltipraz in human hepatocytes.

Résumé

Oltipraz, a synthetic derivative of the cruciferous vegetable product 1,2-dithiole-3-thione, is considered as a potent chemoprotectant. Previously, we have demonstrated that CYP2B6 expression is induced in cultured human hepatocytes by a 24h treatment with oltipraz. The aim of this study was to further determine mechanisms involved in the regulation of CYP2B6 by this compound. An increase of CYP2B6 mRNA is observed after a 4h exposure and maximum induction is reached after 24h. The rapid induction of CYP2B6 mRNA in oltipraz-treated cells suggests a transcriptional activation of corresponding gene. To test this hypothesis, we performed transient transfections with constructs containing the CYP2B6 gene 5'-flanking region upstream of the luciferase gene in order to measure the transcriptional activity of CYP2B6 gene in human hepatoma HepG2 cells, in absence or presence of oltipraz. The results demonstrate that transcriptional activation of CYP2B6 gene is mediated mainly by the pregnane X receptor (PXR) and the Phenobarbital Responsive Element Module (PBREM). The nuclear factor-erythroid 2-related factor 2 (Nrf2) and an antioxidant responsive element (ARE), located upstream the PBREM, might also have a role in this activation but their involvement remains unclear. Despite increasing CYP2B6 apoprotein levels in human hepatocytes, oltipraz has little effect, if any, on testosterone 16beta-hydroxylation which is catalyzed by CYP2B6. This can be explained by a dose-dependent inhibition of CYP2B6 activity in presence of oltipraz as demonstrated with human hepatocyte microsomes. Altogether, this study provides the first demonstration of PXR involvement in oltipraz transcriptional activation of CYP2B6 gene and of the inhibitory effect of oltipraz on CYP2B6 activity.

Domaines

Toxicologie

Dates et versions

hal-00666115 , version 1 (03-02-2012)

Identifiants

Citer

Amélie Piton, Claudine Rauch, Sophie Langouet, André Guillouzo, Fabrice Morel. Involvement of pregnane X receptor in the regulation of CYP2B6 gene expression by oltipraz in human hepatocytes.. Toxicology in Vitro, 2010, 24 (2), pp.452-9. ⟨10.1016/j.tiv.2009.09.025⟩. ⟨hal-00666115⟩
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