Format

Send to

Choose Destination
Arch Toxicol. 2017 Jun;91(6):2425-2441. doi: 10.1007/s00204-016-1907-4. Epub 2016 Dec 22.

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

Author information

1
Department of Pharmacology and Toxicology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands.
2
Department of Pharmacology and Toxicology, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands. R.Godschalk@maastrichtuniversity.nl.

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 (pHe) of 7.8, 7.0, 6.5, 6.0 and 5.5) for 6, 24 and 48 h. In most incubations (pHe 7.0-6.5), the pH in the medium returned to the physiological pH 7.8 after 48 h, but at the lowest pH (pHe < 6.0), this recovery was incomplete. Similar changes were observed for the intracellular pH (pHi). 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 (pHe 7.8) for both cell lines. Cytochrome P450 (CYP1A1/CYP1B1) expression and its activity (ethoxyresorufin-O-deethylase activity) were repressed at low pHe 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 pHe 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 pHe. After 48 h, higher B[a]P-DNA adduct levels and γ-H2AX foci were observed at low pH samples than at pHe 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.

KEYWORDS:

Acidic pH; Benzo[a]pyrene; Cytochrome P450 (CYP1A1); DNA damage; NER

PMID:
28005143
PMCID:
PMC5429366
DOI:
10.1007/s00204-016-1907-4
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center