FK506 INCREASES PERMEABILITY IN RAT INTESTINE BY INHIBITING MITOCHONDRIAL-FUNCTION

Background & Aims: Under normal physiological conditions, the intestin e presents an adenosine triphosphate (ATP)-dependent barrier to lumina l contents. Disruption of this barrier function can occur when cellula r metabolism is compromised. This study examined the effects of FK506 on intestinal permeability and enterocyte metabolic function in Lewis rats. Methods: Rats were administered FK506 at a dose of 0.1, 0.5, or 2 mg/kg on alternate days for 6 weeks. Intestinal permeability was ass essed by measuring urinary recovery of Tc-99m-diethylenetriamine penta cetate, and electrophysiological conductance measurements were perform ed in Ussing chambers. Metabolic function was assessed in isolated ent erocytes by measuring total ATP and CO2 release from [C-14]pyruvate an d [C-14]glucose. Results: Rats treated with FK506 showed a dose-depend ent reduction in weight gain as well as increased in vivo and in vitro intestinal permeability. There was no difference in plasma creatinine or urinary output. Changes in permeability correlated with reduced AT P levels and CO2 release because of diminished mitochondrial function. Lactate production, as a measure of glycolytic activity, was not alte red by FK506. Conclusions: In a dose-dependent manner, FK506 treatment in rats reduces weight gain, increases intestinal permeability, and d ecreases the ability of the small intestine to use glucose as an energ y source.