Leukotriene C 4 metabolism by hepatoma cells and liver

Abstract

The metabolism of the glutathionyl leukotriene LTC 4 in the mercapturic acid pathway was studied in suspensions of AS-30D hepatoma cells and hepatocytes, as well as in vivo in the bile duct-cannulated rat and in primates. 1. 1.|Isolated hepatocytes actively took up cysteinyl leukotrienes and metabolized LTC 4 not only to LTD 4 and LTE 4 but also to N-acetyl-LTE 4 and to metabolites more polar than LTC 4. 2. 2.|AS-30D hepatoma cells are deficient in the transport system for the uptake of cysteinyl leukotrienes. Peptide cleavage of LTC 4 to LTD 4 and LTE 4 was catalyzed by ectoenzymes of these cells. Inactivation of γ-glutamyl-transferase by acivicin and inhibition of LTD 4 dipeptidase by penicillamine largely prevented further catabolism of LTC 4 and LTD 4, respectively. 3. 3.|[ 3H]LTC 4 injected i.v. into rats was rapidly eliminated from the circulating blood, taken up by the liver, and excreted into bile where 77% of the administered radioactivity was recovered within 1 hr. The biliary LTC 4 metabolites included LTD 4, N-acetyl-LTE 4, and metabolites more polar than LTC 4. 4. 4.|Inhibition of [ 3H]LTC 4 metabolism in vivo by i.v. penicillamine shifted the pattern of biliary cysteinyl leukotrienes; an extended half-life of [ 3H]LTD 4 was associated with a retarded formation of N-acetyl-LTE 4 and of polar metabolites. 5. 5.|Endogenous cysteinyl leukotrienes elicited by trauma were measured after HPLC separation by radioimmunologic analysis in plasma and bile of rats. The biliary concentration of these leukotrienes was up to 100 times as great as in plasma. N-Acetyl-LTE 4 was the predominant endogenous metabolite in rat bile. 6. 6.|In the monkey Macaca fascicularis, cysteinyl leukotrienes were predominantly eliminated from blood via the liver into bile; renal excretion amounted to about 50% of the hepatobiliary elimination. Absorption of cysteinyl leukotrienes from the intestine resulted in enterohepatic circulation of these mediators. 7. 7.|Metabolites of [ 3H]LTE 4 injected i.v. in the monkey were analyzed in bile and urine. In addition to polar metabolites and a small percentage of [ 3H]LTD 4, [ 3H]LTE 4 was a predominant metabolite particularly in bile. LTE 4 was also the major endogenous cysteinyl leukotriene detected by radioimmunologic analysis in monkey bile. 8. 8.|LTE 4 was the predominant endogenous cysteinyl leukotriene measured in human bile in patients suffering from acute pancreatitis. The detected amounts of LTE 4 may be sufficient to induce known phenomena associated with acute pancreatitis including the shock-like reaction.