Background~Aims: 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 e 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 5-1ipoxygenase, 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.

-galactosamine plus LTD 4 , 3 suggesting that LTD 4 is directly Cysteinyl-leukotrienes can cause cholestasis and liver daminvolved in the mediation of liver damage. age when administered at nanomolar concentrations. UsingPrevious studies from our laboratory and from other the isolated and perfused rat liver we analyzed whether Sgroups, using isolated and perfused rat liver, have shown that adenosyl-L-methionine (SAMe) may protect this organ against the administration of leukotriene C 4 or LTD 4 , at nanomolar the noxious effects of leukotriene-D 4 (LTD 4 ). We observed concentrations, increases the perfusion pressure and induces that a 2 nmol bolus of this compound decreased bile flow cholestasis. [4][5][6] Very little is known on the mechanism under-(012.6% { 1.6%, P õ .02), and bile salt excretion (023.5%lying the cholestatic effect of cLTs, and, although leuko-{ 2.2%, P õ .02; both compared with baseline values), caused trienes are thought to be implicated in the cholestasis accomthe release of glutamic-oxaloacetic transaminase (GOT) and panying sepsis and inflammatory processes, 7,8 there are few lactic dehygrogenase (LDH) to the hepatic effluent, and indata on substances that can protect the liver against the chocreased significantly the perfusion pressure as compared with lestatic and toxic effects of cLTs. a control group not receiving LTD 4 (6.0 { 1.1 vs. 0.2 { 0.02 S-adenosyl-L-methionine (SAMe) is a naturally occurring mm hg, respectively; P õ .001). The cholestatic effect of LTD 4 metabolite that originates from methionine and adenosine was attenuated by infusion of SAMe which, at rates of 67 triphosphate through the SAMe synthetase pathway. 9 It has and 100 mg/min, totally prevented the decrease in bile salt been shown that SAMe has a protective role in experimental excretion. Likewise, in SAMe infused livers, the release to the cholestasis induced by alcohol, 10 acetaminophen, 11 D-galaceffluent of GOT and LDH was lower than in the group receivtosamine, 12 carbon tetrachloride, 13 or ethinyl estradiol. 14 In ing LTD 4 only, and was even lower than in the control group.this study we analyze whether SAMe may alleviate the choleWe also found that the increase in perfusion pressure induced static, cytotoxic, and hemodynamic effects induced by LTD 4 by LTD 4 was prevented by SAMe in a dose-dependent manner.on the isolated and perfused rat liver. Of interest, SAMe increased the biliary excretion of the eicosanoid in a dose-related fashion. We conclude that SAMe reverts MATERIALS AND METHODS the cholestatic, cytotoxic, and hemodynamic effects of LTD 4 on the liver, and that these protective effects might be partly 1 A significant increase in the pro-celona, Spain). All other chemicals were purchased from Merck duction of cLTs occurs in some experimental models of (Darmstadt, Germany).Livers were isolated from male Wistar rats (range, 240-255 g fulminant hepatitis, as those induced by frog virus 3 2 or Dbody weight), and they were used in a recirculating antegrade perfugalactosamine plus endotoxin. 3 Moreov...