Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen.
Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ2, and delta 12-PGJ2, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA2 and delta 12-PGJ2 in primary cultures of purified rat hepatocytes. As a model ligand, [3H]PGA1 bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 microM (low affinity). The high-affinity binding of [3H]PGA1 was 9- and approximately 13-fold more avid than the binding of the conventional fatty acid ligands, oleic acid and arachidonic acid, respectively. The abilities of different prostaglandins to compete with the high-affinity binding of [3H]PGA1 correlated with their growth inhibitory activities reported previously and here. The growth inhibitory cyclopentenone prostaglandins (PGA1, PGA2, delta 12-PGJ2, and PGJ2) were the best competitive ligands, intermediate competitors were the weak growth inhibitors PGE1 and PGD2, and the poorest competitors were PGE2 and PGF2 alpha, which stimulate rather than inhibit DNA synthesis in rat hepatocytes in primary culture. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.
Khan
S H
SH
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111.
Sorof
S
S
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism; D006131:Growth Inhibitors / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D015230:Prostaglandin D2 / Q000378:metabolism* / Q000031:analogs & derivatives; D011453:Prostaglandins / Q000378:metabolism*; D011454:Prostaglandins A / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344
D002352:Carrier Proteins; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D006131:Growth Inhibitors; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011453:Prostaglandins; D011454:Prostaglandins A; C037112:9-deoxy-delta-9-prostaglandin D2; C040810:9-deoxy-9,10-didehydro-12,13-didehydro-13,14-dihydroprostaglandin D2; D015073:2-Acetylaminofluorene; C100008:prostaglandin A2; D015230:Prostaglandin D2; C100573:prostaglandin A1