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

    27 Citations (Scopus)

    Abstract

    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
    Volume27
    Issue number2
    DOIs
    Publication statusPublished - 2012

    Keywords

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

    ASJC Scopus subject areas

    • Pharmacology
    • Pharmaceutical Science
    • Pharmacology (medical)

    Fingerprint Dive into the research topics of 'Polycyclic aromatic hydrocarbons activate CYP3A4 gene transcription through human pregnane X receptor'. Together they form a unique fingerprint.

    Cite this