Journal article
Induction of cytochrome P450 1A1 in MCF-7 human breast cancer cells by 4-chlorobiphenyl (PCB3) and the effects of its hydroxylated metabolites on cellular apoptosis
Environment international, Vol.36(8), pp.935-941
2010
DOI: 10.1016/j.envint.2009.06.012
PMCID: PMC2904404
PMID: 19604582
Abstract
Several studies suggest an involvement of PCBs in breast cancer formation, but the results are ambiguous and the mechanisms not clear. We propose that local activation of cytochrome P450 enzymes, CYP1A1 and CYP1B1 by PCB3, may generate active metabolites which affect apoptosis and thereby promote mammary carcinogenesis. To test this hypothesis MCF-7 human breast cancer cells were exposed to 300
nM PCB3 and its hydroxylated metabolites, 4OH-PCB and 3,4diOH-PCB3. The enzyme activity for CYP1A1 was assayed using the EROD assay, and CYP1A1 and CYP1B1 protein expression by western blotting. PCB3 increased CYP1A1 activity (~
1.5fold) and protein levels within 6
h after exposure. No effect on CYP1B1 protein expression was observed. The effects of PCB3 and both its metabolites on staurosporine-induced apoptosis were determined by measuring DNA fragmentation using ELISA and TUNEL assays, and by measuring caspase-8 and caspase-9 activity. We found that PCB3 and both of its hydroxylated metabolites had no effect on caspase-8 and caspase-9 activity when cells were grown in medium deprived of estrogen, but reduced caspase-9 activity when cells were grown in medium supplemented with serum containing estradiol. Interestingly, a decrease of DNA fragmentation was observed upon treatment with 3,4diOH-PCB3 in both culture conditions, suggesting that 3,4diOH-PCB3 affects a caspase-independent pathway of cell death. In summary, interactions of PCB3 and its metabolites with estradiol by yet unknown mechanisms inhibit caspase 9-related apoptosis and additional, other death pathways are affected by the catechol metabolite 3,4diOH-PCB3. These anti-apoptotic effects and the change in metabolic activity may contribute to the carcinogenic effect of PCBs.
Details
- Title: Subtitle
- Induction of cytochrome P450 1A1 in MCF-7 human breast cancer cells by 4-chlorobiphenyl (PCB3) and the effects of its hydroxylated metabolites on cellular apoptosis
- Creators
- Anna Ptak - Department of Physiology and Toxicology of Reproduction, Chair of Animal Physiology, Institute of Zoology, Jagiellonian University, Krakow, PolandGabriele Ludewig - University of Iowa, Department of Occupational and Environmental Health, College of Public Health, 100 Oakdale Campus 124 IREH, Iowa City, IA 52242-5000, USAAgnieszka Rak - Department of Physiology and Toxicology of Reproduction, Chair of Animal Physiology, Institute of Zoology, Jagiellonian University, Krakow, PolandWeronika Nadolna - Department of Physiology and Toxicology of Reproduction, Chair of Animal Physiology, Institute of Zoology, Jagiellonian University, Krakow, PolandMichał Bochenek - National Research Institute of Animal Production, Department of Biotechnology of Animal Reproduction, Balice, PolandEwa L Gregoraszczuk - Department of Physiology and Toxicology of Reproduction, Chair of Animal Physiology, Institute of Zoology, Jagiellonian University, Krakow, Poland
- Resource Type
- Journal article
- Publication Details
- Environment international, Vol.36(8), pp.935-941
- DOI
- 10.1016/j.envint.2009.06.012
- PMID
- 19604582
- PMCID
- PMC2904404
- NLM abbreviation
- Environ Int
- ISSN
- 0160-4120
- eISSN
- 1873-6750
- Publisher
- Elsevier Ltd
- Language
- English
- Date published
- 2010
- Academic Unit
- Occupational and Environmental Health; Iowa Superfund Research Program
- Record Identifier
- 9983997348702771
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