URSODEOXYCHOLIC ACID INHIBITS THE INDUCTION OF NITRIC-OXIDE SYNTHASE

Ursodeoxycholic acid was recently recognized as an effective agent in the treatment of primary biliary cirrhosis. Since the beneficial effec t of ursodeoxycholic acid therapy appears to be mediated in part by an immune mechanism, we evaluated the effects of ursodeoxycholic acid on the synthesis of nitric oxide (NO), elevated production of which coul d be important in the pathogenesis of autoimmunity. Ursodeoxycholic ac id (0.1-1000 mu M) inhibited NO production by bacterial lipopolysaccha ride-activated J774 macrophages in a concentration-dependent fashion, but the cytotoxicity was also evident at higher concentrations (250 an d 1000 mu M). Ursodeoxycholic acid did not have any effect on the acti vity of NO synthase that had already been induced. Treatment with lipo polysaccharide led to a significant expression of NO synthase mRNA tha t was significantly reduced by ursodeoxycholic acid. Findings indicate d that ursodeoxycholic acid inhibited NO synthesis by inhibiting the i nduction of NO synthase, rather than its catalytic activity. Ursodeoxy cholic acid therapy may exert a beneficial effect, in part, by attenua ting the production of NO.