leukotriene-e4 and Liver-Diseases

The significance of cysteinyl leukotrienes was investigated in patients with liver diseases by measurements of leukotriene E4 and N-acetyl-leukotriene E4 in urine. A marked increase of renal cysteinyl leukotriene excretion was observed in patients with cirrhosis without and with ascites, intrahepatic cholestasis, and obstructive jaundice as compared with healthy subjects (leukotriene E4: means 82, 264, 221 and 142 versus 40 nmol/mol creatinine, respectively; N-acetyl-leukotriene E4: means 25, 64, 61 and 47 versus 13 nmol/mol creatinine, respectively). The urinary concentration of leukotriene E4 was positively correlated with the one of N-acetyl-leukotriene E4 (r = 0.81, p < 0.001). In patients with cirrhosis, the excretion of cysteinyl leukotrienes was strongly increased in patients in Child-Turcotte stage C as compared with those in Child-Turcotte stages A and B. In patients with intrahepatic cholestasis and in those with obstructive jaundice, the excretion of leukotriene E4 plus N-acetyl-leukotriene E4 was positively correlated with total serum bilirubin. In patients with cirrhosis and in those with obstructive jaundice, the cysteinyl leukotrienes in urine were negatively correlated with creatinine clearance. The elevated renal excretion of cysteinyl leukotrienes decreased after biliary drainage in patients with obstructive jaundice. These data support the concept that increased urinary excretion of cysteinyl leukotrienes in patients with cirrhosis is due to a reduced functional liver mass and that in patients with cholestasis it is mainly due to an impaired elimination into the biliary tract that results in a diversion to renal excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Bilirubin; Cholestasis; Cholestasis, Intrahepatic; Chromatography, High Pressure Liquid; Creatinine; Cysteine; Drainage; Female; Humans; Leukotriene E4; Liver Cirrhosis; Liver Diseases; Male; Middle Aged; Radioimmunoassay; Regression Analysis

Uptake, metabolism and biliary elimination of infused cysteinyl leukotrienes were investigated in single-pass perfused rat liver. Hypoxia did not impair uptake of infused [3H]leukotriene C4, but inhibited biliary excretion of radioactivity by about 50% compared with normoxic control experiments. In addition, the leukotriene metabolite pattern in bile was profoundly altered and was characterized in hypoxia by a 75% to 80% decrease of both leukotriene C4 and polar metabolites, representing omega-oxidation products, whereas the appearance of leukotriene D4 in bile was not affected. Reoxygenation was followed by a marked increase of biliary excretion of polar metabolites, indicating that leukotrienes taken up and stored in the liver cells during the hypoxic period now underwent omega-oxidation with subsequent elimination of the omega-oxidized products. Hypoxia also inhibited the biliary excretion of radioactivity after [3H]leukotriene E4 addition because of an almost complete absence of omega-oxidation products in bile, whereas N-acetyl-leukotriene E4 excretion was not affected. Induction of liver injury by carbon tetrachloride treatment decreased single-pass uptake of [3H]leukotriene C4 by 30%, and only 36% of the radioactivity taken up by the liver was eliminated into bile within 1 hr, compared with 78% in normal livers. The pattern of biliary leukotriene metabolites, however, was not significantly different. Lowering the pH in the perfusion medium from 7.4 to 7.1 had no effect on uptake, metabolism or biliary elimination of infused [3H]leukotriene C4. The data show that hypoxia and experimental liver injury, but not acidosis, impair hepatic processing of cysteinyl leukotrienes. Thus, in leukotriene-induced shock syndromes, leukotriene elimination and inactivation may be impaired giving rise to a "vicious circle."

Topics: Acidosis; Animals; Bile; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Hypoxia; In Vitro Techniques; Leukotriene E4; Leukotrienes; Liver Diseases; Male; Perfusion; Rats; Rats, Inbred Strains; SRS-A

Topics: Animals; Calcimycin; Cells, Cultured; Kupffer Cells; Leukotriene E4; Liver Diseases; Rats; Rats, Inbred Strains; SRS-A