Rasmussen Martin Krøyer, Daujat-Chavanieu Martine, Gerbal-Chaloin Sabine
IRMB, INSERM, University of Montpellier, Montpellier, F-34290, France; Department of Food Science, Aarhus University, Tjele, Denmark.
IRMB, INSERM, University of Montpellier, Montpellier, F-34290, France; CHU Montpellier, Institute for Regenerative Medicine and Biotherapy, Montpellier, F-34290, France.
Toxicol Lett. 2017 Aug 5;277:1-8. doi: 10.1016/j.toxlet.2017.05.029. Epub 2017 May 29.
The role of the cross-talk between nuclear receptors in the regulation of Cytochrome P450 expression in the liver is well-documented. Most studies have focused on the cross-talk between the pregnane X receptor (PXR) and other receptors, such as the constitutive androstane receptor. However, cross-talk between PXRs and aryl hydrocarbon receptors (AhRs) has also been suggested, but reports regarding this cross-talk are conflicting. In the present study, we treated HepaRG and primary human hepatocytes (PHHs) with both a strong (TCDD) and weak (3-methylindole; 3MI) AhR activator to investigate their impact on PXR-regulated expression of CYP3A4. Moreover, we investigated the effect of co-activation of PXR, using rifampicin, and AhR, using TCDD and 3MI, on the regulation of CYP3A4 induction. We also investigated whether knockdown of AhR using siRNA affected the basal expression of PXR and CYP3A4 and induction of CYP3A4 by rifampicin, TCDD and 3MI. The results showed that the treatment of HepaRG cells, but not of PHHs, with AhR activators decreased mRNA expression of CYP3A4 and PXR. Moreover, in both HepaRG and PHHs, AhR activation decreased rifampicin-induced expression of CYP3A4 mRNA. Knock-down of AhR in PHHs increased both basal and rifampicin-induced expression of CYP3A4 mRNA. In conclusion, the presented results suggested that the cross-talk between PXR and AhR plays a role in the regulation of CYP3A4 gene expression.
核受体之间的相互作用在肝脏细胞色素P450表达调控中的作用已有充分记载。大多数研究集中在孕烷X受体（PXR）与其他受体之间的相互作用，如组成型雄甾烷受体。然而，也有研究表明PXR与芳烃受体（AhR）之间存在相互作用，但关于这种相互作用的报道相互矛盾。在本研究中，我们用强效（TCDD）和弱效（3-甲基吲哚；3MI）AhR激活剂处理HepaRG细胞和原代人肝细胞（PHH），以研究它们对PXR调控的CYP3A4表达的影响。此外，我们研究了使用利福平共同激活PXR以及使用TCDD和3MI共同激活AhR对CYP3A4诱导调控的影响。我们还研究了使用小干扰RNA（siRNA）敲低AhR是否会影响PXR和CYP3A4的基础表达以及利福平、TCDD和3MI对CYP3A4的诱导作用。结果表明，用AhR激活剂处理HepaRG细胞而非PHH会降低CYP3A4和PXR的mRNA表达。此外，在HepaRG细胞和PHH中，AhR激活均降低了利福平诱导的CYP3A4 mRNA表达。在PHH中敲低AhR会增加CYP3A4 mRNA的基础表达和利福平诱导的表达。总之，本研究结果表明PXR与AhR之间的相互作用在CYP3A4基因表达调控中发挥作用。
