Acidic cellular microenvironment modifies carcinogen-induced DNA damage and repair.

ABSTRACT: Chronic inflammation creates an acidic microenvironment, which plays an important role in cancer development. To investigate how low pH changes the cellular response to the carcinogen benzo[a]pyrene (B[a]P), we incubated human pulmonary epithelial cells (A549 and BEAS-2B) with nontoxic doses of B[a]P using culturing media of various pH's (extracellular pH (pH_e) of 7.8, 7.0, 6.5, 6.0 and 5.5) for 6, 24 and 48 h. In most incubations (pH_e 7.0-6.5), the pH in the medium returned to the physiological pH 7.8 after 48 h, but at the lowest pH (pH_e < 6.0), this recovery was incomplete. Similar changes were observed for the intracellular pH (pH_i). We observed that acidic conditions delayed B[a]P metabolism and at t = 48 h, and the concentration of unmetabolized extracellular B[a]P and B[a]P-7,8-diol was significantly higher in acidic samples than under normal physiological conditions (pH_e 7.8) for both cell lines. Cytochrome P450 (CYP1A1/CYP1B1) expression and its activity (ethoxyresorufin-O-deethylase activity) were repressed at low pH_e after 6 and 24 h, but were significantly higher at t = 48 h. In addition, a DNA repair assay showed that the incision activity was ~80% inhibited for 6 h at low pH_e and concomitant exposure to B[a]P. However, at t = 48 h, the incision activity recovered to more than 100% of the initial activity observed at neutral pH_e. After 48 h, higher B[a]P-DNA adduct levels and ?-H2AX foci were observed at low pH samples than at pH_e 7.8. In conclusion, acidic pH delayed the metabolism of B[a]P and inhibited DNA repair, ultimately leading to increased B[a]P-induced DNA damage.

SUBMITTER: Shi Q 

PROVIDER: S-EPMC5429366 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature