2013
Smerdová, Lenka; Neča, Jiří; Svobodová, Jana; Topinka, Jan; Schmuczerová, Jana; Kozubík, Alois; Machala, Miroslav; Vondráček, Jan
In: Toxicology, vol. 314, no. 1, pp. 30–38, 2013, ISSN: 1879-3185 0300-483X, (Place: Ireland).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon Hydroxylases/*biosynthesis/genetics, ATP Binding Cassette Transporter, Benzo(a)pyrene/*metabolism, Blotting, Cell Line, Conditioned, Culture Media, CYP1B1, Cytochrome P-450 CYP1B1, Cytokines/metabolism, DNA adducts, Inflammation, Inflammation Mediators/*pharmacology, metabolism, Oxidoreductases Acting on Aldehyde or Oxo Group Donors/biosynthesis/genetics, Polycyclic aromatic hydrocarbons, Pulmonary Alveoli/cytology/drug effects/*metabolism, Rats, Real-Time Polymerase Chain Reaction, RNA, Small Interfering, Subfamily B/biosynthesis/genetics, Tandem Mass Spectrometry, Transfection, Western
@article{smerdova_inflammatory_2013,
title = {Inflammatory mediators accelerate metabolism of benzo[a]pyrene in rat alveolar type II cells: the role of enhanced cytochrome P450 1B1 expression.},
author = {Lenka Smerdová and Jiří Neča and Jana Svobodová and Jan Topinka and Jana Schmuczerová and Alois Kozubík and Miroslav Machala and Jan Vondráček},
doi = {10.1016/j.tox.2013.09.001},
issn = {1879-3185 0300-483X},
year = {2013},
date = {2013-12-01},
journal = {Toxicology},
volume = {314},
number = {1},
pages = {30–38},
abstract = {Long-term deregulated inflammation represents one of the key factors contributing to lung cancer etiology. Previously, we have observed that tumor necrosis factor-α (TNF-α), a major pro-inflammatory cytokine, enhances genotoxicity of benzo[a]pyrene (B[a]P), a highly carcinogenic polycyclic aromatic hydrocarbon, in rat lung epithelial RLE-6TN cells, a model of alveolar type II cells. Therefore, we analyzed B[a]P metabolism in RLE-6TN cells under inflammatory conditions, simulated using either recombinant TNF-α, or a mixture of inflammatory mediators derived from activated alveolar macrophage cell line. Inflammatory conditions significantly accelerated BaP metabolism, as evidenced by decreased levels of both parent B[a]P and its metabolites. TNF-α altered production of the metabolites associated with dihydrodiol-epoxide and radical cation pathways of B[a]P metabolism, especially B[a]P-dihydrodiols, and B[a]P-diones. We then evaluated the role of cytochrome P450 1B1 (CYP1B1), which is strongly up-regulated in cells treated with B[a]P under inflammatory conditions, in the observed effects. The siRNA-mediated CYP1B1 knock-down increased levels of B[a]P and reduced formation of stable DNA adducts, thus confirming the essential role of CYP1B1 in B[a]P metabolism under inflammatory conditions. TNF-α also reduced expression of aldo-keto reductase 1C14, which may compete with CYP1B1 for B[a]P-7,8-dihydrodiol and divert it from the formation of ultimate B[a]P dihydrodiol epoxide. Together, the present data suggests that the CYP1B1-catalyzed metabolism of polycyclic aromatic hydrocarbons might contribute to their enhanced bioactivation and genotoxic effects under inflammatory conditions.},
note = {Place: Ireland},
keywords = {Animals, Aryl Hydrocarbon Hydroxylases/*biosynthesis/genetics, ATP Binding Cassette Transporter, Benzo(a)pyrene/*metabolism, Blotting, Cell Line, Conditioned, Culture Media, CYP1B1, Cytochrome P-450 CYP1B1, Cytokines/metabolism, DNA adducts, Inflammation, Inflammation Mediators/*pharmacology, metabolism, Oxidoreductases Acting on Aldehyde or Oxo Group Donors/biosynthesis/genetics, Polycyclic aromatic hydrocarbons, Pulmonary Alveoli/cytology/drug effects/*metabolism, Rats, Real-Time Polymerase Chain Reaction, RNA, Small Interfering, Subfamily B/biosynthesis/genetics, Tandem Mass Spectrometry, Transfection, Western},
pubstate = {published},
tppubtype = {article}
}
Long-term deregulated inflammation represents one of the key factors contributing to lung cancer etiology. Previously, we have observed that tumor necrosis factor-α (TNF-α), a major pro-inflammatory cytokine, enhances genotoxicity of benzo[a]pyrene (B[a]P), a highly carcinogenic polycyclic aromatic hydrocarbon, in rat lung epithelial RLE-6TN cells, a model of alveolar type II cells. Therefore, we analyzed B[a]P metabolism in RLE-6TN cells under inflammatory conditions, simulated using either recombinant TNF-α, or a mixture of inflammatory mediators derived from activated alveolar macrophage cell line. Inflammatory conditions significantly accelerated BaP metabolism, as evidenced by decreased levels of both parent B[a]P and its metabolites. TNF-α altered production of the metabolites associated with dihydrodiol-epoxide and radical cation pathways of B[a]P metabolism, especially B[a]P-dihydrodiols, and B[a]P-diones. We then evaluated the role of cytochrome P450 1B1 (CYP1B1), which is strongly up-regulated in cells treated with B[a]P under inflammatory conditions, in the observed effects. The siRNA-mediated CYP1B1 knock-down increased levels of B[a]P and reduced formation of stable DNA adducts, thus confirming the essential role of CYP1B1 in B[a]P metabolism under inflammatory conditions. TNF-α also reduced expression of aldo-keto reductase 1C14, which may compete with CYP1B1 for B[a]P-7,8-dihydrodiol and divert it from the formation of ultimate B[a]P dihydrodiol epoxide. Together, the present data suggests that the CYP1B1-catalyzed metabolism of polycyclic aromatic hydrocarbons might contribute to their enhanced bioactivation and genotoxic effects under inflammatory conditions.
2003
Hoferová, Zuzana; Vacek, Antonín; Hofer, Michal; Macková, Nadezda O.; Soucek, Karel; Egyed, Alena; Fedorocko, Peter
Tumor-host interactions accompanying the growth of the G:5:113 fibrosarcoma in the mouse: possibilities for a new therapeutic approach? Journal Article
In: Cancer investigation, vol. 21, no. 2, pp. 227–236, 2003, ISSN: 0735-7907, (Place: England).
Abstract | Links | BibTeX | Tags: Animals, Cell Count, Cell Cycle/*physiology, Cell Division, Cell Survival/*physiology, Conditioned, Culture Media, Cultured, Fibrosarcoma/blood/*pathology, Granulocytes/pathology, Inbred C3H, Leukocyte Count, Mice, Tumor Cells
@article{hoferova_tumor-host_2003,
title = {Tumor-host interactions accompanying the growth of the G:5:113 fibrosarcoma in the mouse: possibilities for a new therapeutic approach?},
author = {Zuzana Hoferová and Antonín Vacek and Michal Hofer and Nadezda O. Macková and Karel Soucek and Alena Egyed and Peter Fedorocko},
doi = {10.1081/cnv-120016419},
issn = {0735-7907},
year = {2003},
date = {2003-04-01},
journal = {Cancer investigation},
volume = {21},
number = {2},
pages = {227–236},
abstract = {The experiments were aimed at describing in detail some interactions between a solid tumor growing from subcutaneously transplanted G:5:113 fibrosarcoma cells in vivo and its mouse host. The tumor was found to elevate significantly the number of granulocytes in the peripheral blood of the host after having achieved the volume of about 1 cm3 (day 40 after transplantation). Blood plasma from fibrosarcoma-bearing mice stimulated proliferation of progenitor cells for granulocytes and macrophages (GM-CFC) in vitro and suppressed growth of G:5:113 cell population in culture. Interestingly, both effects were observable as early as week 1 when the tumor was still macroscopically invisible and unpalpable. Conditioned medium from cultures of G:5:113 fibrosarcoma cells stimulated proliferation of GM-CFC in vitro. These findings might represent a starting point for studies aimed at designing new therapeutic approaches for the treatment of fibrosarcoma.},
note = {Place: England},
keywords = {Animals, Cell Count, Cell Cycle/*physiology, Cell Division, Cell Survival/*physiology, Conditioned, Culture Media, Cultured, Fibrosarcoma/blood/*pathology, Granulocytes/pathology, Inbred C3H, Leukocyte Count, Mice, Tumor Cells},
pubstate = {published},
tppubtype = {article}
}
The experiments were aimed at describing in detail some interactions between a solid tumor growing from subcutaneously transplanted G:5:113 fibrosarcoma cells in vivo and its mouse host. The tumor was found to elevate significantly the number of granulocytes in the peripheral blood of the host after having achieved the volume of about 1 cm3 (day 40 after transplantation). Blood plasma from fibrosarcoma-bearing mice stimulated proliferation of progenitor cells for granulocytes and macrophages (GM-CFC) in vitro and suppressed growth of G:5:113 cell population in culture. Interestingly, both effects were observable as early as week 1 when the tumor was still macroscopically invisible and unpalpable. Conditioned medium from cultures of G:5:113 fibrosarcoma cells stimulated proliferation of GM-CFC in vitro. These findings might represent a starting point for studies aimed at designing new therapeutic approaches for the treatment of fibrosarcoma.