Butyrate alters expression of cytochrome P450 1A1 and metabolism of benzo[a]pyrene via its histone deacetylase activity in colon epithelial cell models

Ondřej Zapletal, Zuzana Tylichová, Jiří Neča, Jiří Kohoutek, Miroslav Machala, Alena Milcová, Michaela Pokorná, Jan Topinka, Mary Pat Moyer, Jiřina Hofmanová, Alois Kozubík, Jan Vondráček

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Butyrate, a short-chain fatty acid produced by fermentation of dietary fiber, is an important regulator of colonic epithelium homeostasis. In this study, we investigated the impact of this histone deacetylase (HDAC) inhibitor on expression/activity of cytochrome P450 family 1 (CYP1) and on metabolism of carcinogenic polycyclic aromatic hydrocarbon, benzo[a]pyrene (BaP), in colon epithelial cells. Sodium butyrate (NaBt) strongly potentiated the BaP-induced expression of CYP1A1 in human colon carcinoma HCT116 cells. It also co-stimulated the 7-ethoxyresorufin-O-deethylase (EROD) activity induced by the 2,3,7,8-tetrachlorodibenzo-p-dioxin, a prototypical ligand of the aryl hydrocarbon receptor. Up-regulation of CYP1A1 expression/activity corresponded with an enhanced metabolism of BaP and formation of covalent DNA adducts. NaBt significantly potentiated CYP1A1 induction and/or metabolic activation of BaP also in other human colon cell models, colon adenoma AA/C1 cells, colon carcinoma HT-29 cells, or in NCM460D cell line derived from normal colon mucosa. Our results suggest that the effects of NaBt were due to its impact on histone acetylation, because additional HDAC inhibitors (trichostatin A and suberanilohydroxamic acid) likewise increased both the induction of EROD activity and formation of covalent DNA adducts. NaBt-induced acetylation of histone H3 (at Lys14) and histone H4 (at Lys16), two histone modifications modulated during activation of CYP1A1 transcription, and it reduced binding of HDAC1 to the enhancer region of CYP1A1 gene. This in vitro study suggests that butyrate, through modulation of histone acetylation, may potentiate induction of CYP1A1 expression, which might in turn alter the metabolism of BaP within colon epithelial cells.

Original languageEnglish (US)
Pages (from-to)2135-2150
Number of pages16
JournalArchives of Toxicology
Volume91
Issue number5
DOIs
StatePublished - May 1 2017
Externally publishedYes

Keywords

  • Butyrate
  • CYP1A1
  • Colon epithelial cells
  • DNA adducts
  • Histone deacetylases
  • Polycyclic aromatic hydrocarbons

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

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