Interaction of LY171883 and other peroxisome proliferators with fatty-acid-binding protein isolated from rat liver.
Fatty-acid-binding protein (FABP) is a 14 kDa protein found in hepatic cytosol which binds and transports fatty acids and other hydrophobic ligands throughout the cell. The purpose of this investigation was to determine whether LY171883, a leukotriene D4 antagonist, and other peroxisome proliferators bind to FABP and displace an endogenous fatty acid. [3H]Oleic acid was used to monitor the elution of FABP during chromatographic purification. [14C]LY171883 had a similar elution profile when substituted in the purification, indicating a common interaction with FABP. LY171883 and its structural analogue, LY189585, as well as the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate, bezafibrate and WY14,643, displaced [3H]oleic acid binding to FABP. Analogues of LY171883 that do not induce peroxisome proliferation only weakly displaced oleate binding. [3H]Ly171883 bound directly to FABP with a Kd of 10.8 microM, compared with a Kd of 0.96 microM for [3H]oleate. LY171883 binding was inhibited by LY189585, clofibric acid, ciprofibrate and bezafibrate. These findings demonstrate that peroxisome proliferators, presumably due to their structural similarity to fatty acids, are able to bind to FABP and displace an endogenous ligand from its binding site. Interaction of peroxisome proliferators with FABP may be involved in perturbations of fatty acid metabolism caused by these agents as well as in the development of the pleiotropic response of peroxisome proliferation.
Cannon
J R
JR
Toxicology Division, Lilly Research Laboratories, Eli Lilly and Company, Greenfield, IN 46140.
Eacho
P I
PI
D000098:Acetophenones / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism*; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D058607:Fibric Acids; D008297:Male; D008830:Microbodies / Q000187:drug effects*; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D019301:Oleic Acid; D009829:Oleic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013189:SRS-A / Q000737:chemistry / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D000098:Acetophenones; D002352:Carrier Proteins; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D058607:Fibric Acids; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009829:Oleic Acids; D011743:Pyrimidines; D013189:SRS-A; D013777:Tetrazoles; D019301:Oleic Acid; D002995:Clofibric Acid; C006253:pirinixic acid; C044660:LY 171883; C019304:ciprofibrate; D001629:Bezafibrate