title: Polycyclic aromatic hydrocarbons activate CYP3A4 gene transcription through human pregnane X receptor.
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-small interfering 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.
authors.affiliation: Department of Environmental Health Science, Tohoku Pharmaceutical University, Sendai. ta-kuma@tohoku-pharm.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kumagai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Sasaki
authors.forename: Shuhei
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyairi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nagata
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000502:physiology*; D013638:Tars / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology
chemical_list: D011084:Polycyclic Aromatic Hydrocarbons; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013638:Tars; C024746:tobacco tar; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human