Document Detail

Experimental characterization of the mechanism of perfluorocarboxylic acids' liver protein bioaccumulation: the key role of the neutral species.
MedLine Citation:
PMID:  20821618     Owner:  NLM     Status:  MEDLINE    
Perfluorocarboxylic acids (PFCAs) of chain length greater than seven carbon atoms bioconcentrate in the livers of fish. However, a mechanistic cause for the empirically observed increase in the bioconcentration potential of PFCAs as a function of chain length has yet to be determined. To this end, recombinant rat liver fatty acid-binding protein (L-FABP) was purified, and its interaction with PFCAs was characterized in an aqueous system at pH 7.4. Relative binding affinities of L-FABP with PFCAs of carbon chain lengths of five to nine were established fluorimetrically. The energetics, mechanism, and stoichiometry of the interaction of perfluorooctanoic acid (PFOA) with L-FABP were examined further by isothermal titration calorimetry (ITC) and electrospray ionization combined with tandem mass spectrometry (ESI-MS/MS). Perfluorooctanoic acid was shown to bind to L-FABP with an affinity approximately an order of magnitude less than the natural ligand, oleic acid, and to have at least 3:1 PFOA:L-FABP stoichiometry. Two distinct modes of PFOA binding to L-FABP were observed by ESI-MS/MS analysis; in both cases, PFOA binds solely as the neutral species under typical physiological pH and aqueous concentrations of the anion. A comparison of their chemical and physical properties with other well-studied biologically relevant chemicals showed that accumulation of PFCAs in proteins as the neutral species is predictable. For example, the interaction of PFOA with L-FABP is almost identical to that of the acidic ionizing drugs ketolac, ibuprofen, and warfarin that show specificity to protein partitioning with a magnitude that is proportional to the K(OW) (octanol-water partitioning) of the neutral species. The experimental results suggest that routine pharmacochemical models may be applicable to predicting the protein-based bioaccumulation of long-chain PFCAs.
Mark W Woodcroft; David A Ellis; Steven P Rafferty; Darcy C Burns; Raymond E March; Naomi L Stock; Kyle S Trumpour; Janet Yee; Kim Munro
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Environmental toxicology and chemistry / SETAC     Volume:  29     ISSN:  1552-8618     ISO Abbreviation:  Environ. Toxicol. Chem.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-09-07     Completed Date:  2010-12-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8308958     Medline TA:  Environ Toxicol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1669-77     Citation Subset:  IM    
Copyright Information:
Copyright 2010 SETAC
Department of Chemistry, Trent University, 1600 West Bank Drive, Peterborough, Ontario K9J 7B8, Canada.
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MeSH Terms
Carboxylic Acids
Fatty Acid-Binding Proteins / chemistry,  metabolism
Fishes / metabolism
Fluorocarbons / chemistry,  metabolism*
Liver / chemistry,  metabolism*
Octanoic Acids / chemistry,  metabolism
Water Pollutants, Chemical / chemistry,  metabolism
Reg. No./Substance:
0/Carboxylic Acids; 0/Fatty Acid-Binding Proteins; 0/Fluorocarbons; 0/Octanoic Acids; 0/Water Pollutants, Chemical; 335-67-1/perfluorooctanoic acid

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