TAUROCHOLATE-STIMULATED LEUKOTRIENE C-4 BIOSYNTHESIS AND LEUKOTRIENE C-4-STIMULATED CHOLERESIS IN ISOLATED RAT-LIVER

Background/Aims: Cysteinyl-containing leukotrienes seem to exert a cho lestatic effect. However, leukotriene inhibitors were found to reduce bile salt efflux in isolated rat hepatocytes, suggesting a role for le ukotrienes in bile flow formation, Methods: In the isolated rat liver, the effects of two different concentrations of leukotriene C-4 on bil e flow and bile salt excretion are analyzed, as well as the possible e ffect of taurocholate on the hepatic production of cysteinyl-containin g leukotrienes. Results: Leukotriene C-4 (0.25 fmol) increased bile sa lt excretion (+22.2%; P < 0.05), whereas a much higher dose (0.25 x 10 (6) fmol) showed the known cholestatic effect, reducing bile salt excr etion (-25.9%; P < 0.01). These dose-dependent biphasic effects were s pecific because they could be prevented by the simultaneous administra tion of cysteinyl-containing leukotriene antagonists. On the other han d, taurocholate administration induced a dose-dependent increase in bi liary excretion of cysteinyl-containing leukotrienes. Furthermore, tau rocholate increased messenger RNA levels of 5-lipoxygenase, a key enzy me in leukotriene biosynthesis. Taurocholate increase of hepatocyte in tracellular calcium was not significant, suggesting that taurocholate effects are not mediated by stimulation of calcium metabolism. Conclus ions: These results constitute evidence for the existence of a positiv e feedback mechanism by which bile salts stimulate the synthesis of le ukotrienes that, in turn, stimulate bile salt excretion.