Hepatic metabolism of prostacyclin (PGI 2) in the rabbit: Formation of a potent novel inhibitor of platelet aggregation

Abstract

Metabolism of [9- 3H]-PGI 2 was studied in the isolated Tyrode's perfused rabbit liver. Five products, four radioactive and one non-radioactive, were identified in the perfusate: 19-hydroxy-6-keto-PGF 1α, 6-keto-PGF 1α, dinor-6-keto-PGF 1α, pentanor PGF 1α and a 6-keto-PGE 1-like substance. The first two, 19-hydroxy-6-keto-PGF 1α and 6-keto-PGF 1α, represented 5% and 45% respectively, of the total radioactivity; the last two accounted for 39%. The presence of dinor and pentanor derivatives of 6-keto-PGF 1α indicated that β -oxidation and oxidative-decarboxylation occurs in the liver as the major metabolic pathway of PGI 2. One non-radioactive metabolite which co-migrated with authentic 6-keto-PGE 1 was found to inhibit platelet aggregation, having a potency similar to authentic 6-keto-PGE 1, and its effect can be eliminated by boiling and by alkali treatment. This metabolite, having similar Rf value on TLC and biological behavior as 6-keto-PGE 1, may arise from oxidation of 6-keto-PGF 1α via the 9-hydroxyprostaglandin dehydrogenase pathway, as suggested by recovery of tritiated water in the aqueous phase of the perfusate. This material, a potent inhibitor of platelet aggregation, may arise from PGI 2 or its hydrolysis product, 6-keto-PGF 1α.