Informace o publikaci
Inflammatory mediators accelerate metabolism of benzo[a]pyrene in rat alveolar type II cels: the role of enhanced cytochrome P450 1B1 expression
| Název česky | Zánětlivé mediátory urychlují metabolismus benzo[a]pyrenu v potkaních alveolárních buňkách typu II : role zvýšené exprese cytochromu P450 1B1 |
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| Autoři | |
| Rok publikování | 2013 |
| Druh | Článek v odborném periodiku |
| Časopis / Zdroj | Toxicology |
| Fakulta / Pracoviště MU | |
| Citace | |
| www | http://www.sciencedirect.com/science/article/pii/S0300483X13002382 |
| Doi | http://dx.doi.org/10.1016/j.tox.2013.09.001 |
| Obor | Farmakologie a lékárnická chemie |
| Klíčová slova | Inflammation; CYP1B1; Polycyclic aromatic hydrocarbons; Metabolism; DNA adducts |
| Přiložené soubory | |
| Popis | Long-term deregulated inflammation represents one of the key factors contributing to lung cancer etiology. Previously, we have observed that tumor necrosis factor-alpha (TNF-alpha), 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 INF-alpha, 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. INF-alpha 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-alpha also reduced expression of aldo-keto reductase 104, 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. |