2-bromooctanoic-acid and Colitis--Ulcerative

The effects of sodium butyrate and sodium bromo-octanoate (an inhibitor of beta oxidation) on colonic mucus glycoprotein (mucin) synthesis have been assessed using tissue from colonic resection samples. Epithelial biopsy specimens were incubated for 16 hours in RPMI 1640 with glutamine, supplemented with 10% fetal calf serum and N-acetyl-[3H]-glucosamine ([3H]-Glc NAc), and differing concentrations of sodium butyrate. Incorporation of [3H] Glc NAc into mucin by normal epithelium at least 10 cm distant from colonic cancer was increased in the presence of sodium butyrate in a dose dependent manner, with maximum effect (476%) at a concentration of 0.1 mM (number of specimens = 24 from six patients, p < 0.001). The increase in response to butyrate was not seen when specimens were incubated in the presence of the beta oxidation inhibitor sodium bromo-octanoate 0.05 M. The striking increase in mucin synthesis that results when butyrate is added to standard nutrient medium suggests that this may be an important mechanism affecting the rate of mucin synthesis in vivo and may also explain the therapeutic effect of butyrate in colitis.

Topics: Adult; Aged; Butyrates; Butyric Acid; Caprylates; Chromatography, Agarose; Colitis, Ulcerative; Colon; Culture Techniques; Dose-Response Relationship, Drug; Female; Humans; Kinetics; Male; Mucins

There is some evidence that failure of fatty acid or beta-oxidation in the epithelium of the colonic mucosa is associated with the development of ulcerative colitis. We tested the hypothesis that inhibition of fatty acid oxidation in the colonic mucosa of the rat reproduces the histological, clinical and biochemical lesions of acute ulcerative colitis of man. A specific inhibitor of beta-oxidation, sodium 2-bromo-octanoate, was instilled rectally for 5 days or exposed to isolated colonic epithelial cells which were subsequently tested for their ability to beta-oxidize n-butyrate. Weight loss, bloody diarrhoea and histological lesions occurred with 2-bromo-octanoate treated rats but not control animals. Ketogenesis and 14CO2 production was inhibited by 2-bromo-octanoate. Of 12 animals mucosal ulceration developed in six out of eight surviving animals and in all four animals that died. Ulceration, mucus cell depletion, vessel dilatation and increases of inflammatory cells were the most prominent histological changes. Present observations indicate that inhibition of beta-oxidation produces acute colitis and suggests that inhibition of beta-oxidation is primary rather than secondary in the genesis of ulcerative colitis. A search for agents producing such biochemical lesions in man should be undertaken.

Topics: Animals; Antioxidants; Body Weight; Caprylates; Carbon Dioxide; Colitis, Ulcerative; Colon; Fatty Acids; Female; Intestinal Mucosa; Ketone Bodies; Male; Rats; Rats, Inbred Strains