Modulation of benzo[a]pyrene–DNA adduct formation by CYP1 inducer and inhibitor
© The Author(s) 2017
Received: 27 December 2016
Accepted: 15 February 2017
Published: 10 April 2017
Benzo[a]pyrene (BaP) is a well-studied pro-carcinogen that is metabolically activated by cytochrome P450 enzymes. Cytochrome P4501A1 (CYP1A1) has been considered to play a central role in the activation step, which is essential for the formation of DNA adducts. This enzyme is strongly induced by many different chemical agents, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which binds to the aryl hydrocarbon receptor (AhR). Therefore, AhR activators are suspected to have the potential to aggravate the toxicity of BaP through the induction of CYP1A1. Besides, CYP1A1 inhibitors, including its substrates, are estimated to have preventive effects against BaP toxicity. However, strangely, increased hepatic BaP–DNA adduct levels have been reported in Cyp1a1 knockout mice. Moreover, numerous reports describe that concomitant treatment of AhR activators reduced BaP–DNA adduct formation. In an experiment using several human cell lines, TCDD had diverse modulatory effects on BaP–DNA adducts, both enhancing and inhibiting their formation. In this review, we focus on the factors that could influence the BaP–DNA adduct formation. To interpret these complicated outcomes, we propose a hypothesis that CYP1A1 is a key enzyme for both generation and reduction of (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), the major carcinogenic intermediate of BaP. Conversely, CYP1B1 is thought to contribute only to the metabolic activation of BaP related to carcinogenesis.
KeywordsDNA adduct Benzo[a]pyrene Aryl hydrocarbon receptor Cytochrome P450
Influence of benzo[a]pyrene DNA adduct by various compounds
Modulation of BaP adduct
de Waard et al. 
Caco-2 (human colorectal carcinoma)
Gelhaus SL 
H358 (human lung carcinoma)
Wu Q et al. 
Harrigan JA et al. 
rat lung and liver (ex vivo)
Shiizaki K et al. 
HepG2 (human hepatoma)
Hodek P et al. 
rat liver/small intestine
Chang KW et al. 
A427 and CL3 (human lung carcinoma)
AhR antagonist/CYP1A1 inhibitor
Mohebati A et al. 
AhR antagonist/CYP1A1 inhibitor (AhR antagonist)
Takemura H et al. 
MCF-7 (human breast adenocarcinoma)
Wen X et al. 
SCC-9 (human squamous carcinoma)
Kang ZC et al. 
Vanhees K et al. 
mouse liver (ex vivo)
Revel A et al. 
Sehgal A et al. 
mouse liver and lung
CYP1A1 inhibitor/(AhR agonist)
Kleiner HE et al. 
MCF-7 (human breast adenocarcinoma)
After summarizing the enzymes involved in BaP metabolism, we provide a range of experimental results about the effects of AhR modulators on BaP adduct formation. Finally, this review focuses on the expression profile of CYP isoforms in cells in order to interpret these complicated, paradoxical, and enigmatic results.
BaP catalytic enzymes and their induction by AhR
Several mammalian enzymes involved in BaP metabolism have been reported [31–34]. CYP1A1, 1A2, 1B1, 2C9, 2C19, and 3A4 are considered to be the oxidation enzymes of BaP. Among these enzymes, BaP metabolites that can form DNA adducts were generated by CYP1A1, 1B1, and 2C19 . The products generated by these CYP subtypes are considered to be benzo[a]pyrene 7,8-epoxide and BPDE. CYP1A1 is expressed ubiquitously and CYP2C19 is expressed specifically in the liver, while CYP1B1 is expressed in extrahepatic tissues [35, 36]. AhR regulates the inducible expression of the CYP1A1 and 1B1 genes, but not that of CYP2C19 . Therefore, the expression of these two enzymes would contribute to the modulation of BaP–DNA adduct formation in the presence of additional AhR ligands other than BaP. Another enzyme involved in BaP metabolism is epoxide hydrolase (EPHX). Benzo[a]pyrene-7,8-epoxide, an CYP1A1 or CYP1B1 metabolite of BaP, is transformed to benzo[a]pyrene-7,8-dihydrodiol by microsomal epoxide hydrolase (EPHX1). Then, benzo[a]pyrene-7,8-dihydrodiol is catalyzed to BPDE by CYP1A1 or CYP1B1. EPHX1 and CYP are considered to generate BPDE in a coordinated manner . EPHX1 gene regulation by the transcription factor GATA-4 has been reported, but EPHX1 is not an AhR target gene [24, 39]. For the conjugating enzymes, UDP-glucuronosyltransferase (UGT) subtypes UGT1A1 and UGT1A6 and glutathione transferase (GST) subtypes GSTA1, GSTA2, GSTA4, GSTM1, GSTP1, and microsomal GST play roles in generating hydrophilic conjugates. Among these enzymes, UGT1A1 induced by TCDD via AhR was reported. Overall, CYP1A1, CYP1B1, and UGT1A1 are most likely to influence BaP–DNA adduct formation via AhR activators.
Suppression of BaP adduct formation by TCDD
Alteration of BaP adduct formation by CYP substrates and inhibitors
AhR modulators showed a wide variety of both protective and aggravative effects on BaP adduct formation, as shown in Fig. 1. Indirubin, one of the endogenous AhR ligands , showed a slight preventive effect. However, the phyto-anthraquinone alizarin , which is also regarded as an AhR agonist, did not show any preventive effects. These results can be interpreted as follows. Indirubin and alizarin are not only AhR agonists but also CYP1A1 substrates, which could represent competitive inhibition. From the hypothesis that CYP1A1 activity is crucial for BaP–DNA adduct formation, these chemicals would have dual functions for CYP1A1 and not simply act like TCDD. On the other hand, BaP–DNA adducts were increased by concomitant exposure to BaP and omeprazole. Omeprazole, a drug for treating gastro-esophageal reflux disease, activates AhR without binding as a ligand [42, 43]. Omeprazole-mediated CYP1A1 induction requires more than 12 h after omeprazole treatment and it is slower than the BaP-mediated CYP1A1 induction . Moreover, omeprazole has inhibitory effects on CYP1A1 as a competitive inhibitor . Thus, the increase of BaP adducts by omeprazole would be a result that reflected only CYP1A1 inhibition, but not CYP1A1 induction. An AhR antagonist, α-naphthoflavone, also increased BaP adduct formation, and the enhancing effects would be due to CYP1A1 inhibition rather than the effects as an AhR antagonist. In our previous studies, BPDE-induced DNA adducts were reduced by recombinant CYP1A1, and additional α-naphthoflavone induced recovery from this reduction . This in vitro assay system was unrelated to AhR-mediated gene transcriptional regulation, so the results support the hypothesis that CYP1A1 can metabolically reduce BPDE. The enhancement of BaP–DNA adducts by CYP1A1 inhibitors including substrates would be the result of inhibition of the metabolic elimination of BPDE.
Expression of CYP isoforms and BaP–DNA adduct formation
CYP1A1 and 1B1 exhibit various tissue distributions. For example, CYP1B1 is abundant in kidney and bone marrow, but these organs scarcely express CYP1A1. Thus, alteration by AhR agonist to the BaP-adduct formation might depend on the expression profile of CYP1A1 and CYP1B1 in the target tissue. Uno et al. reported tissue-specific differences of BaP toxicity in CYP1A1- and/or CYP1B1-deficient mice . They also reported the importance of BaP detoxification by CYP1A1 . In addition, Shi et al. reported the differences in the role of CYP1A1 in BaP detoxification between the small intestine and liver by generating tissue-specific knockout mouse models . The insights obtained from in vitro studies can consistently explain the results of these in vivo studies.
At present, we cannot definitively conclude that AhR ligands enhance BaP toxicity in the human body. However, we can predict their effects in organ exhibiting biased expression of CYP1 enzymes, for example, predominant expression of CYP1B1 in lung, and scarce expression of CYP1B1 in liver [54, 55]. This could explain some of the organ differences in the incidence of cancer caused by smoking and may contribute to developing chemoprevention using AhR ligands or CYP inhibitors.
The action of the AhR modulators on BaP adduct formation is the composite result of the several effects including induction, reduction and inhibition of the CYP1 enzymes. CYP1A1 is involved in both the generation and the degradation of BPDE, while CYP1B1 only has activity in generating BPDE. The effects of AhR modulators on BaP–DNA adduct formation depend on the CYP1A1/1B1 expression profile of cells.
Aryl hydrocarbon receptor
AhR nuclear translocator
The authors would like to thank Yukari Totsuka, National Cancer Center Research Institute, and Togo Ikuta, Saitama Cancer Center, for giving the opportunity to prepare for this review.
This research was supported by Grants-in-Aid for Scientific Research (S) No. 18101002 and (B) No. 24310047 (TY), No. 18101003 (MK), and (C) No. 15 K06849 (KS) from the Japan Society for the Promotion of Science.
Availability of data and materials
This is not applicable to this review. The authors did not generate the data but relied on published studies.
KS and TY participated in research design and wrote or contributed to the writing of the review. TY and MK contributed to establishing the experimental methods and KS designed and carried out the experiments. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This research does not involve human subjects, human material, human data or animal experimental data.
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