Taurocholate-stimulated leukotriene C4 biosynthesis and leukotriene C4-stimulated choleresis in isolated rat liver.
OBJECTIVE
Cysteinyl-containing leukotrienes seem to exert a cholestatic effect. However, leukotriene inhibitors were found to reduce bile salt efflux in isolated rat hepatocytes, suggesting a role for leukotrienes in bile flow formation.


METHODS
In the isolated rat liver, the effects of two different concentrations of leukotriene C4 on bile flow and bile salt excretion are analyzed, as well as the possible effect of taurocholate on the hepatic production of cysteinyl-containing leukotrienes.


RESULTS
Leukotriene C4 (0.25 fmol) increased bile salt 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 excretion (-25.9%; P < 0.01). These dose-dependent biphasic effects were specific because they could be prevented by the simultaneous administration of cysteinyl-containing leukotriene antagonists. On the other hand, taurocholate administration induced a dose-dependent increase in biliary excretion of cysteinyl-containing leukotrienes. Furthermore, taurocholate increased messenger RNA levels of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Taurocholate increase of hepatocyte intracellular calcium was not significant, suggesting that taurocholate effects are not mediated by stimulation of calcium metabolism.


CONCLUSIONS
These results constitute evidence for the existence of a positive feedback mechanism by which bile salts stimulate the synthesis of leukotrienes that, in turn, stimulate bile salt excretion.
Rodríguez-Ortigosa
C M
CM
Department of Medicine, University Clinic and Medical School, University of Navarra, Pamplona, Spain.
Vesperinas
I
I
Qian
C
C
Quiroga
J
J
Medina
J F
JF
Prieto
J
J
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics; D001483:Base Sequence; D001646:Bile / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D017997:Leukotriene C4 / Q000096:biosynthesis* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid / Q000494:pharmacology*
D002756:Cholagogues and Choleretics; D002867:Chromones; D017997:Leukotriene C4; D013656:Taurocholic Acid; C006312:FPL 55712; D001094:Arachidonate 5-Lipoxygenase; D002118:Calcium