Interactions of fluorochemicals with rat liver fatty acid-binding protein.
Liver-fatty acid binding protein (L-FABP) is an abundant intracellular lipid-carrier protein. The hypothesis that perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and certain related perfluorooctanesulfonamide-based fluorochemicals (PFOSAs) can interfere with the binding affinity of L-FABP for fatty acids was tested. The relative effectiveness of PFOA, PFOS, N-ethylperfluorooctanesulfonamide (N-EtFOSA), N-ethylperfluorooctanesulfonamido ethanol (N-EtFOSE), and of the strong peroxisome proliferator Wyeth-14643 (WY) to inhibit 11-(5-dimethylaminonapthalenesulphonyl)-undecanoic acid (DAUDA) binding to-L-FABP was determined. The dissociation constant (Kd) of the DAUDA-L-FABP complex was 0.47 nM. PFOS exhibited the highest level of inhibition of DAUDA-L-FABP binding in the competitive binding assays, followed by N-EtFOSA, WY, and, with equal IC(50)s, N-EtFOSE and PFOA. The in vitro data presented in this study support the hypothesis that these fluorochemicals may interfere with the binding of fatty acids or other endogenous ligands to L-FABP. Furthermore, this work provides evidence to support the hypothesis that displacement of endogenous ligands from L-FABP may contribute to toxicity in rodents fed these fluorochemicals.
Luebker
Deanna J
DJ
3M Medical Department, Corporate Toxicology, 3M Center Building 220-2E-02, Saint Paul, MN 55144, USA. djluebker@mmm.com
Hansen
Kris J
KJ
Bass
Nathan M
NM
Butenhoff
John L
JL
Seacat
Andrew M
AM
D000465:Algorithms; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000737:chemistry*; D004591:Electrophoresis, Polyacrylamide Gel; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism; D005456:Fluorescent Dyes; D005466:Fluorocarbons / Q000737:chemistry*; D008099:Liver / Q000737:chemistry*; D008297:Male; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D013050:Spectrometry, Fluorescence; D021241:Spectrometry, Mass, Electrospray Ionization
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; D005456:Fluorescent Dyes; D005466:Fluorocarbons; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C006253:pirinixic acid