Efficient transport and biotransformation of dipeptide-like tyrosine/phenylalanine-conjugated phenolic amide esters in THP-1 cells and PBMCs: A potential means for transporting compounds inside monocytes/macrophages

Recent studies suggest that dipeptide-like tyrosine/phenylalanine-conjugated phenolic amide compounds may contain several biological activities including anti-inflammatory activity. However, there is currently no information about their transport and biotransformation in monocytes/macrophages involved in inflammation process. The objective of this study was to investigate cell transport and biotransformation of the phenolic amides and esters in monocyte/macrophage-like cells. Cell transport and biotransformation of the phenolic amides and esters (N-coumaroylphenylalanine, N-caffeoylphenylalanine, N-feruloylphenylalanine, N-coumaroyltyrosine, N-caffeoyltyrosine, N-feruloyltyrosine and their O-methyl esters) were investigated in THP-1 cells and PBMCs using HPLC, cellular and kinetics methods In THP-1 cells, the phenolic amides were not transported significantly, but their O-methyl esters were transported significantly (P < 0.02). Also, the transport of the esters was found to be sodium-independent and pH-dependent. Among the tested esters, N-feruloylphenylalanine-O-methyl ester showed the highest uptake (Km of 25 µM), and the uptake was inhibited by PepT1/2 substrate and blocker (GlySar and enalapril) in THP-1 cells. Particularly, enalapril competitively inhibited the uptake with Ki of 560 µM. The data also showed that N-feruloylphenylalanine-O-methyl ester and N-feruloyltyrosine-O-methyl ester could be biotransformed into parent phenolic amides in THP-1 cells. Similarly, the ester compounds were also found to be transported and biotransformed in PBMCs. The data suggest that dipeptide-like tyrosine/phenylalanine-conjugated phenolic amide esters may be transported and biotransformed in THP-1 cells and PBMCs.