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

  • Toxicokinetics and Metabolism
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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.

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Acknowledgements

This study was supported by the Czech Science Foundation (Project No. 13-09766S to A.K.), the Czech Ministry of Agriculture (RO 0515 to M.M.) and Internal Grant Agency of the Ministry of Health of the Czech Republic (NT14599-3/2013 to J.K.). The authors acknowledge the assistance provided by the Research Infrastructure NanoEnviCz, supported by the Ministry of Education, Youth and Sports of the Czech Republic under Project No. LM2015073. The authors wish to thank prof. Chris Paraskeva (School of Cellular and Molecular Medicine, University of Bristol, Bristol, UK) for kindly providing AA/C1 cell line. The expert technical assistance of Radek Fedr, Iva Lišková and Martina Urbánková is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Cytokinetics, Institute of Biophysics, The Czech Academy of Sciences, Královopolská 135, 61265, Brno, Czech Republic

    Ondřej Zapletal, Zuzana Tylichová, Jiřina Hofmanová, Alois Kozubík & Jan Vondráček

  2. Department of Experimental Biology, Faculty of Science, Masaryk University, 61137, Brno, Czech Republic

    Ondřej Zapletal & Zuzana Tylichová

  3. Department of Chemistry and Toxicology, Veterinary Research Institute, 62100, Brno, Czech Republic

    Jiří Neča, Jiří Kohoutek & Miroslav Machala

  4. Department of Genetic Ecotoxicology, Institute of Experimental Medicine, The Czech Academy of Sciences, 14220, Prague, Czech Republic

    Alena Milcová, Michaela Pokorná & Jan Topinka

  5. INCELL Corporation LLC, San Antonio, TX, 78249, USA

    Mary Pat Moyer

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  1. Ondřej Zapletal
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Zapletal, O., Tylichová, Z., Neča, J. et al. Butyrate alters expression of cytochrome P450 1A1 and metabolism of benzo[a]pyrene via its histone deacetylase activity in colon epithelial cell models. Arch Toxicol 91, 2135–2150 (2017). https://doi.org/10.1007/s00204-016-1887-4

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