Pregnane X receptor regulates the AhR/Cyp1A1 pathway and protects liver cells from benzo-[]-pyrene-induced DNA damage. Academic Article uri icon


  • Pregnane X receptor (PXR) plays an important role in protecting cells from mutagenic DNA damages induced by endogenous and exogenous toxicants. This protective function is often attributed to the PXR-regulated metabolic detoxification. Here we report a novel potential mechanism that PXR reduces benzo-[]-pyrene(BaP)-induced DNA damage through inhibiting the transcriptional activity of aryl hydrocarbon receptor (AhR) which plays a pivotal role in the bioactivation of BaP. We have utilized three well-characterized cell lines, i.e. Hepa1c1c7, AhR +/+; Bpr lacks AhR obligatory partner ARNT; Tao, lacks AhR, to analyze pivotal role of AhR/ARNT complex in mediating the BaP-induced DNA damages using comet assay (single-cell gel electrophoresis). We found that PXR activation could significantly inhibit BaP-induced DNA damage in the HepG2 cells as well as mouse hepatocytes. Using PXR-null and wild type mouse hepatocytes we showed that PXR activation by pregnenolone 16-carbonitrile (PCN) significantly inhibited BaP-induced DNA damage and this protective effect was abolished in PXR-null hepatocytes. Mechanistically, PXR activation inhibited expression of AhR-target genes for CYP1A1, CYP1B1 and CYP1A2 that are required for BaP biotransformation in cultured liver cells, or in the livers of C57BL/6J mice. Using an AhR-responsive reporter assay as well as chromatin immunoprecipitation assay we found that PXR activation transcriptionally represses AhR-regulated gene expression. Furthermore, we found that PXR directly bound AhR at its DNA-binding domain, and this association may play a role in preventing of the AhR from binding to its target genes as shown in the ChIP assay. Taken together, our study has revealed a novel mechanism by which PXR protects liver cells from BaP-induced DNA damage through inhibiting the BaP biotransformation.

published proceedings

  • Toxicol Lett

altmetric score

  • 0.25

author list (cited authors)

  • Cui, H., Gu, X., Chen, J., Xie, Y., Ke, S., Wu, J., ... Tian, Y.

citation count

  • 23

complete list of authors

  • Cui, Hongmei||Gu, Xinsheng||Chen, Jingshu||Xie, Ying||Ke, Sui||Wu, Jing||Golovko, Andrei||Morpurgo, Benjamin||Yan, Chunhong||Phillips, Timothy D||Xie, Wen||Luo, Jianyuan||Zhou, Zhijun||Tian, Yanan

publication date

  • January 2017