The influence of endotoxin on the hepatic metabolism and elimination of 3H-leukotriene C4 (LTC,) and 3H-leukotriene E4 was studied in the single-pass perfused rat liver. Endotoxin (4 mgkg body mass) was injected intraperitoneally 8 to 10 hours before livers were isolated for perfusion. Tritiated leukotriene C4 and leukotriene E4 (10 nmol/L) were infused for 5 minutes, and metabolites in bile were determined by high-pressure liquid chromatography. In livers without endotoxin pretreatment, single-pass uptake of LTCl was 77.3% ? 3.2%, and 73.8% 2 1.8% of the radioactivity taken up was excreted into the bile within 80 minutes. In endotoxin-pretreated livers, LTC4 uptake was 62.8% t 3.5% and only 31.2% 5 1.5% of the radioactivity taken up was eliminated into the bile within 80 minutes. Bile flow was reduced to 0.20 2 0.07 pUg/min, compared with 1.18 2 0.18 pL'g/min in untreated livers. Biliary excretion of infused 3H-LTE4 was also reduced in endotoxin-pretreated livers (31.5% +-6.1% compared with 61.4% t 3.3% without endotoxin pretreatment), whereas uptake was not significantly different. The effect of cellular hydration state on leukotriene processing was also investigated. Anisoosmotic cell volume changes did not influence uptake and biliary excretion of 3H-LTC4 and its metabolism in control livers. In endotoxin-pretreated livers, however, cell swelling induced by hypotonic perfusion media (225 mOsndL) or by 3 mmol/L glutamine increased biliary elimination of the radioactivity taken up by 68% and 54%, respectively. Bile flow was also stimulated (0.31 2 0.09 puglrnin and 0.46 t 0.01 pJJg/min, respectively). Colchicine (5 pmoVL) completely abolished the stimulatory effect of hypotonic perfusion on biliary leukotriene excretion. Hypertonic perfusion decreased leukotriene elimination into bile to 18.1% t 3.8% of the radioactivity taken up and bile flow to 0.11 2 0.04 pUg/min. In livers perfused with hyper-Abbreviations: LT, leukotriene; ATP, adenosine triphosphate.