Polycyclic aromatic hydrocarbons activate CYP3A4 gene transcription through human pregnane X receptor

Takeshi Kumagai, Hiroyuki Suzuki, Takamitsu Sasaki, Shuhei Sakaguchi, Shinichi Miyairi, Yasushi Yamazoe, Kiyoshi Nagata

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


Aryl hydrocarbon receptor (AhR) activators have been shown to induce members of the cytochrome P450 (P450) 1 family. Here we demonstrate that the AhR activators induce CYP3A4 through human pregnane X receptor (PXR). AhR activators, polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) increased CYP3A4 reporter activity and CYP3A4 mRNA expression in HepG2 cells. The CYP3A4 reporter activity was also increased by treatment with cigarette tar. The increased CYP3A4 reporter activity was clearly knocked down by the introduction of human PXR-smallinterfering RNA, but not by that of human AhR-small interfering RNA. The CYP3A4 reporter activity enhanced by overexpression of human PXR was further increased by treatment with PAHs and TCDD as well as by treatment with rifampicin. These results suggest that PAHs contained in cigarette smoke induce CYP3A4 in human liver.

Original languageEnglish
Pages (from-to)200-206
Number of pages7
JournalDrug metabolism and pharmacokinetics
Issue number2
Publication statusPublished - 2012
Externally publishedYes


  • AhR activator
  • CYP3A4 induction
  • PXR
  • Polycyclic aromatic hydrocarbons
  • TCDD

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)


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