Induction of carbonyl reductase 1 (CBR1) expression in human lung tissues and lung cancer cells by the cigarette smoke constituent benzo[a]pyrene.

ABSTRACT: Carbonyl reductase 1 (CBR1) reduces various xenobiotic carbonyl substrates to corresponding alcohol metabolites. Here we demonstrated that benzo[a]pyrene (B[a]P), a potent pro-carcinogen and predominant polycyclic aromatic hydrocarbon (PAH) compound in cigarette smoke and air pollutants, upregulates CBR1 gene expression in vitro and in vivo, and that a proximal xenobiotic response element (XRE) motif (????XRE) mediates the induction effect of B[a]P. First, we observed 46% and 50% increases in CBR1 mRNA and CBR1 protein levels, respectively, in human lung tissue samples from smokers compared to never-smokers. Second, we detected 3.0-fold (p<0.0001) induction of CBR1 mRNA and 1.5-fold (p<0.01) induction of CBR1 protein levels in cells of the human lung cancer cell line A549 incubated with 2.5 ?M B[a]P for 24h. Third, results from experiments with CBR1 promoter constructs indicated that a proximal XRE motif ????XRE) mediates induction of reporter activity in response to B[a]P. Furthermore, we detected enhanced nuclear translocation of aryl hydrocarbon receptor (AhR) following B[a]P exposure in A549 cells. Finally, we demonstrated increased binding of specific protein complexes to ????XRE in nuclear extracts from B[a]P-treated cells and the presence of the AhR/Arnt complex in the specific nuclear protein ????XRE complexes.

SUBMITTER: Kalabus JL 

PROVIDER: S-EPMC3359411 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature