Publication details

Inflammatory mediators accelerate metabolism of benzo[a]pyrene in rat alveolar type II cels: the role of enhanced cytochrome P450 1B1 expression

Authors

ŠMERDOVÁ Lenka NEČA Jiří SVOBODOVÁ Jana TOPINKA Jan SCHMUCZEROVÁ Jana KOZUBÍK Alois MACHALA Miroslav VONDRÁČEK Jan

Year of publication 2013
Type Article in Periodical
Magazine / Source Toxicology
MU Faculty or unit

Faculty of Science

Citation
Web http://www.sciencedirect.com/science/article/pii/S0300483X13002382
Doi http://dx.doi.org/10.1016/j.tox.2013.09.001
Field Pharmacology and pharmaceutical chemistry
Keywords Inflammation; CYP1B1; Polycyclic aromatic hydrocarbons; Metabolism; DNA adducts
Attached files
Description 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.

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