Structure-Based Investigation on the Interaction of Perfluorinated Compounds with Human Liver Fatty Acid Binding Protein

Abstract

Perfluorinated compounds (PFCs) are known to accumulate in liver and induce hepatotoxicity on experimental animals. Liver fatty acid binding protein (L-FABP) is expressed highly in hepatocytes and binds fatty acids. PFCs may bind with FABP and change their ADME and toxicity profile. In the present study, the binding interaction of 17 structurally diverse PFCs with human L-FABP was investigated to assess their potential disruption effect on fatty acid binding. The binding affinity of twelve perfluorinated carboxylic acids (PFCAs), as determined by fluorescence displacement assay, increased significantly with their carbon number from 4 to 11, and decreased slightly when the number was over 11. The three perfluorinated sulfonic acids (PFSAs) displayed comparable affinity, but no binding was detected for the two fluorotelomer alcohols. Circular dichroism results showed that PFC binding induced distinctive structural changes of the protein. Molecular docking revealed that the driving forces for the binding of PFCs with FABP were predominantly hydrophobic and hydrogen-bonding interactions, and the binding geometry was dependent on both the size and rigidity of the PFCs. Based on the binding constant obtained in this work, the possibility of in vivo competitive displacement of fatty acids from FABP by PFCs was estimated.

Long-chain perfluoroalkyl carboxylic acids in Pacific cods from coastal areas in northern Japan: A major source of human dietary exposure

“…2), suggesting different bioaccumulation mechanisms. This result may be explained by previous in vivo and in vitro studies, showing that long-chain PFCAs may accumulate preferentially in liver over lipid-rich tissues due to a high affinity for fatty acid binding proteins in the liver (Fujii et al, 2015;Zhang et al, 2013).…”

Structure–activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor

“…Second, TR binding potency is also dependent on the end group in the order of sulfonate > carboxylate > alcoholic hydroxyl. Several previous studies assessed the binding potency of PFCs with some other proteins, including nuclear receptors such as ER and peroxisome PPARs, transport proteins such as transthyretin, human serum albumin, and fatty acid-binding protein (Benninghoff et al 2011;Chen and Guo 2009;Luebker et al 2002;Weiss et al 2009;Zhang et al 2013). As far as we know, there was no previous study on the binding interaction between PFCs and TR.…”

Toxicokinetics of perfluoroalkyl carboxylic acids with different carbon chain lengths in mice and humans

“…These results suggest that unbound C6 and C7 PFCAs were excreted by glomerular filtration in the kidney, while the ≥C8 PFCAs were mainly eliminated by bile in the liver. At the same time, long alkyl-chain PFCAs (≥C9) may accumulate preferentially in the liver because of their high affinity for liver fatty acid binding proteins 33) . It is already a known fact that the binding affinity of PFCAs increases with longer alkyl chains 33) .…”

“…At the same time, long alkyl-chain PFCAs (≥C9) may accumulate preferentially in the liver because of their high affinity for liver fatty acid binding proteins 33) . It is already a known fact that the binding affinity of PFCAs increases with longer alkyl chains 33) . Further studies are required to understand the large PFCA (≥C8) depositions in the liver.…”