Journal
TOXICOLOGY
Volume 274, Issue 1-3, Pages 42-48Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2010.05.009
Keywords
Benzo[a]pyrene; Chrysoeriol; Cytochrome P450 1 family; DNA adducts; Liquid chromatography-tandem mass; spectrometry
Categories
Funding
- Ministry of Education, Culture, Sports, Science and Technology of Japan [20700601]
- Global COE Program
- Center of Excellence for Innovation in Human Health Sciences
- Ministry of Education, Science, Sports and Culture of Japan
- Grants-in-Aid for Scientific Research [20700601, 21580408] Funding Source: KAKEN
Ask authors/readers for more resources
Cytochrome P450 (CYP) 1 families including CYP1A1,1A2 and 1B1 are well known to be deeply involved in the initiation of several cancers, due to the fact that they activate environmental pro-carcinogens to form ultimate carcinogens. Benzo[a]pyrene (BaP) is one of the major classes of prototypical pro-carcinogen. It is activated by the CYP1 family to its ultimate carcinogenic forms, mainly BaP-7,8-diol-9,10-epoxide(BPDE), and it forms adducts with DNA. This has been recognized to be a major initiation pathway for cancer. Our previous study demonstrated that chrysoeriol, which is a dietary methoxyflavonoid, selectively inhibited CYP1B1 enzymatic activity and might protect the CYP1B1 related-diseases such as breast cancer. In the present study, we further examined the effects of chrysoeriol on the other initiation pathway of cancer relating to the CYP1 family with BaP in human breast cancer MCF-7 cells. The effects of chrysoeriol on the formation of BPDE-DNA adducts were analyzed specifically using the liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. When MCF-7 cells were incubated with 2 mu M BaP for 24 h, three types of BPDE-dG adducts, especially (+)-trans-BPDE-dG as the dominant adduct, were detected. Co-treatment of MCF-7 cells with 10 mu M chrysoeriol and BaP remarkably reduced (+)-trans-BPDE-dG formation. Chrysoeriol (1-10 mu M) dose-dependently inhibited both EROD activity and the gene expressions of CYP1A1, 1B1 and 1A2 stimulated by treatment with BaP. In addition, the same amounts of chrysoeriol significantly inhibited the binding of BaP to the aryl hydrocarbon receptor (AhR), which is the key factor concerning the induction of the CYP1 families. In conclusion, our results clearly indicate that chrysoeriol inhibited the formation of BPDE-DNA adducts via regulation of the AhR pathway stimulated by BaP. As a consequence chrysoeriol may be involved in the chemoprevention of environmental pro-carcinogens such as BaP. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available