Fundamental Toxicological Sciences

Paper Details

Fundamental Toxicological Sciences
Vol. 4 No. 5 October 05, 2017 p.229-239
Original Article
CYP3A4 induction mechanism of polycyclic aromatic hydrocarbons differs from that of rifampicin in PXR binding element
  • Kiyoshi Nagata (Department of Environmental Health Science, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University / nagataki@tohoku-mpu.ac.jp)
Yusuke Aratsu 1) 2) , Reo Odagiri 1) , Rie Shoji 1) , Kouki Watanabe 1) , Takeshi Kumagai 1) , Sawako Shindo 1) , Takamitsu Sasaki 1) 3) , Kiyoshi Nagata 1)
1) Department of Environmental Health Science, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University , 2) Drug Metabolism and Pharmacokinetics Research Laboratories, Central Pharmaceutical Research Institute, Japan tobacco Inc. , 3) Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizoka
Keywords: CYP3A4 induction, Pregnane X receptor, Rifampicin, Polycyclic aromatic hydrocarbons, Dibenz[a,h]anthracene, PXR binding element
Abstracts

CYP3A4 is an important drug-metabolizing enzyme induced by various compounds causing drug-drug interactions. However, the molecular mechanism of CYP3A4 induction is not completely understood. CYP3A4 induction is caused by pregnane X receptor (PXR) through binding to some PXR binding elements. These elements comprise an everted repeat separated by six nucleotides in the promoter region and distal nuclear receptor binding element 1 (dNR-1) as well as the essential distal nuclear receptor binding element for CYP3A4 induction (eNR3A4) in the enhancer region of the CYP3A4 gene. Recently, we found that polycyclic aromatic hydrocarbons including anthracene induce CYP3A4 in HepG2 cells with a different induction profile from that of rifampicin (RF), a typical PXR ligand. When a CYP3A4 reporter plasmid in which the eNR3A4 DNA fragment binds directly to the CYP3A4 promoter (-362 bases) was evaluated in a reporter assay, dibenz[a,h]anthracene (DBA) induced reporter activity, while RF did not. To be induced reporter activity by RF, more 14 nucleotides 5′ upstream of the eNR3A4 (rifampicin eNR3A4: reNR3A4) DNA fragment were required. However, eNR3A4 and reNR3A4 did not respond to recombinant PXR without dNR-1. These results suggest that eNR3A4 and reNR3A4 are necessary for CYP3A4 induction by DBA and RF, respectively, and that dNR-1 is indispensable for full induction through PXR.