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Carcinogenesis |
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084
Procarcinogenic polycyclic aromatic hydrocarbons (PAHs) induce
their own metabolism and activation by binding to the cytosolic aryl
hydrocarbon receptor (AhR), which then translocates to the nucleus and
activates CYP1A1 gene transcription via xenobiotic response
elements (XREs). Although the AhR demonstrates a strict specificity for
planar aromatics, nonplanar
(±)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene
also induced CYP1A1 expression in HepG2 cells over a
delayed timecourse (
6–12 h), suggesting a requirement for
(±)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene
metabolism. Aldo-keto reductase (AKR) inhibitors blocked this effect,
suggesting that benzo(a)pyrene-7,8-dione (BPQ), a planar
PAH o-quinone generated by AKRs, was the downstream
inducer. BPQ was found to be a potent and rapid inducer of CYP1A1, with
an EC50 value in HepG2 cells identical to that of the
parent benzo(a)pyrene. BPQ was a more potent inducer of
CYP1A1 when compared with the 1,6-, 3,6-, and
6,12-benzo(a)pyrene-diones. Multiple PAH
o-quinones caused induction of CYP1A1, demonstrating that
this was a general property of AKR-generated PAH
o-quinones. HepG2-101L cells stably transfected with a
XRE-luciferase construct showed that BPQ activated CYP1A1
transcription via a XRE-dependent mechanism. BPQ failed to induce
CYP1A1 in AhR-deficient and AhR nuclear translocator-deficient murine
hepatoma cell lines and confirmed that induction of CYP1A1 was AhR and
AhR nuclear translocator-dependent. Electrophoretic mobility shift
assays demonstrated the specific appearance of BPQ-activated AhR in the
nucleus, and immunofluorescence studies confirmed that BPQ mediated
nuclear translocation of the AhR. Classical bifunctional inducers
elevate CYP1A1 expression via a XRE and are subsequently
converted by CYP1A1 to electrophiles that induce phase II enzymes via
an electrophilic response element/antioxidant response element. PAH
o-quinones represent a novel class of bifunctional inducer
because they are electrophiles produced by phase II enzymes that
simultaneously induce phase I enzymes via a XRE and phase II enzymes
via a electrophilic response element/antioxidant response element (see
also M. E. Burczynski et al., Cancer Res.,
59: 607–614, 1999). This study shows that the AhR provides
the only known mechanism by which genotoxic PAH o-quinones
generated in the cytosol can be targeted to the nucleus with
specificity.
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