Adaptative metabolic response of human colonic epithelial cells to the adverse effects of the luminal compound sulfide.
Hydrogen sulfide (H(2)S), a bacterial metabolite present in the lumen of the large intestine, is able to exert deleterious effects on the colonic epithelium. The mechanisms involved are still poorly understood, the reported effect of sulfide being its capacity to reduce n-butyrate beta-oxidation in colonocytes. In this work, we studied both the acute effect of the sodium salt of H(2)S on human colonic epithelial cell metabolism and the adaptative response of these cells to the pre-treatment with this agent. Using the human colon carcinoma epithelial HT-29 Glc(-/+) cell model, we found that the acute effect of millimolar concentrations of NaHS was to inhibit l-glutamine, n-butyrate and acetate oxidation in a dose-dependent manner. Using micromolar concentrations of NaHS, a comparable effect but largely reversible was observed for O(2) consumption and cytochrome c oxidase activity. Pre-treatment with 1 mM NaHS induced several adaptative responses. Firstly, increased lactate release and decreased cellular oxygen consumption evidenced a Pasteur-like effect which only partly compensated for the altered mitochondrial ATP production. Thus, a decrease in the proliferation rate with a constant adenylate charge was observed. Secondly, in these pre-treated cells, NaHS induced a hypoxia-like effect on cytochrome c oxidase subunits I and II which were decreased. Thirdly, a mild uncoupling of mitochondrial respiration possibly resulting from an increase of UCP 2 protein was observed. The NaHS antimitotic activity was not due to cellular apoptosis and/or necrosis but to a proportional slowdown in all cell cycle phases. These results are compatible with a metabolic adaptative response of the HT-29 colonic epithelial cells to sulfide-induced O(2) consumption reduction which, through the maintenance of a constant energetic load and an increased mitochondrial proton leak, would participate in the preservation of cellular viability.
Laboratoire de Nutrition et Sécurité Alimentaire, Institut National de la Recherche Agronomique, 78352 Jouy en Josas cedex, France.
Xavier
X
Leschelle
Marc
M
Goubern
Mireille
M
Andriamihaja
Hervé M
HM
Blottière
Elodie
E
Couplan
Maria-Del-Mar
MD
Gonzalez-Barroso
Caroline
C
Petit
Anthony
A
Pagniez
Catherine
C
Chaumontet
Bernard
B
Mignotte
Frédéric
F
Bouillaud
François
F
Blachier
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000008:administration & dosage*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology*
D010100:Oxygen; D006862:Hydrogen Sulfide