title: The deleterious metabolic and genotoxic effects of the bacterial metabolite p-cresol on colonic epithelial cells.
abstract: p-Cresol that is produced by the intestinal microbiota from the amino acid tyrosine is found at millimolar concentrations in the human feces. The effects of this metabolite on colonic epithelial cells were tested in this study. Using the human colonic epithelial HT-29 Glc(-/+) cell line, we found that 0.8mM p-cresol inhibits cell proliferation, an effect concomitant with an accumulation of the cells in the S phase and with a slight increase of cell detachment without necrotic effect. At this concentration, p-cresol inhibited oxygen consumption in HT-29 Glc(-/+) cells. In rat normal colonocytes, p-cresol also inhibited respiration. Pretreatment of HT-29 Glc(-/+) cells with 0.8mM p-cresol for 1 day resulted in an increase of the state 3 oxygen consumption and of the cell maximal respiratory capacity with concomitant increased anion superoxide production. At higher concentrations (1.6 and 3.2mM), p-cresol showed similar effects but additionally increased after 1 day the proton leak through the inner mitochondrial membrane, decreasing the mitochondrial bioenergetic activity. At these concentrations, p-cresol was found to be genotoxic toward HT-29 Glc(-/+) and also LS-174T intestinal cells. Lastly, a decreased ATP intracellular content was observed after 3 days treatment. p-Cresol at 0.8mM concentration inhibits colonocyte respiration and proliferation. In response, cells can mobilize their "respiratory reserve." At higher concentrations, p-cresol pretreatment uncouples cell respiration and ATP synthesis, increases DNA damage, and finally decreases the ATP cell content. Thus, we have identified p-cresol as a metabolic troublemaker and as a genotoxic agent toward colonocytes.
authors.affiliation: UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Andriamihaja
authors.affiliation: UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France.
authors.forename: Annaïg
authors.initials: A
authors.lastname: Lan
authors.affiliation: UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Beaumont
authors.affiliation: INRA, UMR1331, Toxalim, Research Centre in Food Toxicology, F-31027 Toulouse, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Audebert
authors.affiliation: Department of Nutrition, Faculty of Medicine University of Chile, Santiago, Chile.
authors.forename: Ximena
authors.initials: X
authors.lastname: Wong
authors.affiliation: UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France.
authors.forename: Kana
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Yin
authors.affiliation: UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tomé
authors.affiliation: Department of Nutrition, Faculty of Medicine University of Chile, Santiago, Chile.
authors.forename: Catalina
authors.initials: C
authors.lastname: Carrasco-Pozo
authors.affiliation: Department of Nutrition, Faculty of Medicine University of Chile, Santiago, Chile; Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile.
authors.forename: Martin
authors.initials: M
authors.lastname: Gotteland
authors.affiliation: Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China.
authors.forename: Xiangfeng
authors.initials: X
authors.lastname: Kong
authors.affiliation: UMR 914 INRA/AgroParisTech, Nutrition Physiology and Ingestive Behavior, Paris, France. Electronic address: francois.blachier@agroparistech.fr.
authors.forename: François
authors.initials: F
authors.lastname: Blachier
mesh_terms: D003106:Colon / Q000187:drug effects*; D003408:Cresols / Q000633:toxicity*; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects*; D009153:Mutagens / Q000633:toxicity*
chemical_list: D003408:Cresols; D009153:Mutagens; C032538:4-cresol
keywords: Anion superoxide production; Cell proliferation; Genotoxicity; Intestinal microbiota; Large intestine; Mitochondrial oxygen consumption