Prostaglandin uptake and metabolism by the perfused rat liver.
1. The prostaglandins are C20 unsaturated fatty acids which exhibit diverse physiological effects of short duration. We have investigated the speed of removal of PGE(1) and PGF(1alpha) from the circulating blood and their subsequent metabolism by the isolated perfused rat liver.2. Following either a single injection of radiolabelled PGE(1) or PGF(1alpha) into the hepatic artery or portal vein, or recirculation of prostaglandins through the liver for 2.5 h, the distribution of radioactivity within extracts of bile, blood and liver was determined. The nature of the radioactive products of meta-bolism was inferred by comparison of the distribution of radioactivity after injecting carbon and tritium labelled standards, and by thin-layer chromatography, gas-liquid chromatography, ultraviolet and bioassay analysis.3. A single injection of 1-(14)C PGE(1) indicated that the liver could efficiently remove 89-95% of circulating PGE(1) on a single passage. Biliary excretion was excluded as a major route for elimination of unchanged PGE(1), because only 0.3-0.8% of the injected radioactivity was detected in the bile. During recirculation of 1-(14)C PGE(1), 11-19% of the injected radioactivity was detected as exchanged (14)CO(2). The radioactivity detected within liver was identified with further fragments resulting from decarboxylation of PGE(1), which were incorporated into fatty acids and then phospholipids.4. Studies with 5,6-(3)H PGE(1), and comparison with the results obtained using 1-(14)C PGE(1), revealed a 30-fold increase in the percentage of radioactivity excreted into the bile, suggesting that biliary excretion may be a major route for elimination of compounds smaller than C20 prostaglandin. Evidence that the cyclopentane ring was intact was inferred by formation of a PGB compound on treatment with alkali; similar biliary excretion of 9-(3)H PGF(1alpha) also occurred. In addition, the increased radioactivity detected within the liver (37%) and blood (43%) after a single injection of 5,6-(3)H PGE(1) had the solvent partition and thin-layer chromatography properties of PGE(1), but were associated with a less polar compound smaller than the C20 parent structure.5. These results indicate rapid uptake of circulating prostaglandins by the rat liver. Decarboxylation of prostaglandins results in pharmacological inactivation. The products are excreted into the bile and venous effluent. These processes would curtail the duration of effects following prostaglandin injection.In addition, we infer from these results that any physiological action of these ubiquitous endogenous substances is likely to be localized within their tissue of origin.