| Literature DB >> 23845848 |
Claudia Luckert1, Anke Ehlers, Thorsten Buhrke, Albrecht Seidel, Alfonso Lampen, Stefanie Hessel.
Abstract
Metabolic activation of polycyclic aromatic hydrocarbons (PAH) is mediated mainly by cytochrome P₄₅₀ monooxygenases (CYP) CYP1A1, 1A2 and 1B1. Several PAH are known to induce these CYP via aryl hydrocarbon receptor (AhR) signaling. Recently, it was shown that the PAH benzo[a]pyrene (BaP) can induce CYP3A4 as well. The induction was suggested to be mediated by the pregnane X receptor (PXR) rather than AhR. Metabolism by CYP3A4 is only known for dihydrodiol metabolites of PAH but not for their parent compounds. In the present study, a CYP3A4 reporter gene assay, requiring the overexpression of PXR, was used to investigate whether the PAH parent compounds BaP, benzo[c]phenanthrene (BcP) and dibenzo[a,l]pyrene (DBalP) as well as their corresponding phase I metabolites, the respective dihydrodiols and diol epoxides, can induce CYP3A4 promoter activity. BaP, BcP and their dihydrodiols were found to significantly activate the CYP3A4 promoter. Moreover, activation of PXR by all four compounds was detected by using a PXR transactivation assay, supporting that PXR mediates CYP3A4 induction by PAH. Taken together, these results show that both PAH parent compounds as well as their phase I metabolites induce CYP3A4 promoter via the transcription factor PXR.Entities:
Keywords: (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene; (±)-anti-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene; (±)-anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene; (±)-trans-11,12-dihydroxy-11,12-dihydrodibenzo[a,l]pyrene; (±)-trans-3,4-dihydroxy-3,4-dihydrobenzo[c]phenanthrene; (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene; 3-MC; 3-methylcholanthrene; AhR; BaP; BaPD; BaPDE; BcP; BcPD; BcPDE; CAR; CYP; CYP3A4 induction; DBD; DBalP; DBalPD; DBalPDE; DNA-binding domain; DR; ER; GST; LBD; PAH; PPARγ; PXR; PXR responsive element(s); PXRE; Polycyclic aromatic hydrocarbons; Reporter gene assay; UAS; UDP-glucuronosyltransferase(s); UGT; XREM; aryl hydrocarbon receptor; benzo[a]pyrene; benzo[c]phenanthrene; constitutive androstane receptor; cytochrome P(450) monooxygenase(s); dNR; dibenzo[a,l]pyrene; direct repeat; distal nuclear receptor-binding element(s); everted repeat; glutathione S-transferase(s); ligand-binding domain; peroxisome proliferator-activated receptor γ; polycyclic aromatic hydrocarbon(s); pregnane X receptor; qRT-PCR; real-time quantitative PCR; upstream activation sequence; xenobiotic-responsive enhancer module
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Year: 2013 PMID： 23845848 DOI： 10.1016/j.toxlet.2013.06.243
Source DB: PubMed Journal: Toxicol Lett ISSN： 0378-4274 Impact factor: 4.372