S-adenosyl-L-methionine protects the liver against the cholestatic, cytotoxic, and vasoactive effects of leukotriene D4: A study with isolated and perfused rat liver

✍ Scribed by R N Cincu; C M Rodriguez-Ortigosa; I Vesperinas; J Quiroga; J Prieto

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 228 KB
• Volume: 26
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.510260212

✦ Synopsis

D-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. Using

Previous 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 chole-We 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 SAMe was a gift from Europharma (Madrid, Spain). Taurocholic because of a stimulation of the biliary excretion of the leukoacid (sodium salt), methionine, and bovine serum albumin were obtained from Sigma Chemical Co. (St. Louis, MO). Synthetic stan-triene. (HEPATOLOGY 1997;26:330-335.) dards of cLTs were from Cayman Chemical (Ann Arbor, MI), and [ 3 H]LTD 4 was from Amersham (Little Chalfont, UK). Scintillation Cysteinyl-leukotrienes (cLTs), specifically leukotriene C 4 liquid (Normascint F-1) and methanol (high-performance liquid and leukotriene D 4 (LTD 4 ), have been associated with the chromatography [HPLC] grade) were obtained from Scharlau (Bar- induction of liver injury. 1 A significant increase in the procelona, 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 Moreover, a fulminant hepasion system. Liver isolation was as previously described. 4 Briefly, titis similar to that induced by administration of D-galactosthe bile duct was first cannulated with a polyethylene tubing PE-50, amine plus endotoxin can be induced by administration of followed by cannulation of the portal vein with a catheter Abbocath (Abbott, Sligo, Ireland) 16-G. Then, the liver was perfused in situ with oxygenated and heparinized Krebs-Ringer bicarbonate (KRB) buffer at 37ЊC, the vena cava was cut, and the thoracic vena cava was Abbreviations: cLTs, cysteinyl-leukotrienes; LTD4, leukotriene D4; SAMe, S-adenocannulated with a polyethylene cannula (1.5 mm inner diameter), syl-L-methionine; KRB, Krebs-Ringer bicarbonate; RP-HPLC, reverse-phase high-performance liquid chromatography; GOT, glutamic-oxaloacetic transaminase; LDH, lactic defining the final path of perfusion from vena porta to vena cava. dehydrogenase.

At that moment, the liver was transferred to an acrylic platform,