Impact of Intracellular Lipid Binding Proteins on Endogenous and Xenobiotic Ligand Metabolism and Disposition.

The family of intracellular lipid binding proteins (iLBPs) is comprised of 16 members of structurally related binding proteins that have ubiquitous tissue expression in humans. iLBPs collectively bind diverse essential endogenous lipids and xenobiotics. iLBPs solubilize and traffic lipophilic ligands through the aqueous milieu of the cell. Their expression is correlated with increased rates of ligand uptake into tissues and altered ligand metabolism. The importance of iLBPs in maintaining lipid homeostasis is well established. Fatty acid binding proteins (FABPs) make up the majority of iLBPs and are expressed in major organs relevant to xenobiotic absorption, distribution, and metabolism. FABPs bind a variety of xenobiotics including nonsteroidal anti-inflammatory drugs, psychoactive cannabinoids, benzodiazepines, antinociceptives, and peroxisome proliferators. FABP function is also associated with metabolic disease, making FABPs currently a target for drug development. Yet the potential contribution of FABP binding to distribution of xenobiotics into tissues and the mechanistic impact iLBPs may have on xenobiotic metabolism are largely undefined. This review examines the tissue-specific expression and functions of iLBPs, the ligand binding characteristics of iLBPs, their known endogenous and xenobiotic ligands, methods for measuring ligand binding, and mechanisms of ligand delivery from iLBPs to membranes and enzymes. Current knowledge of the importance of iLBPs in affecting disposition of xenobiotics is collectively described. SIGNIFICANCE STATEMENT: The data reviewed here show that FABPs bind many drugs and suggest that binding of drugs to FABPs in various tissues will affect drug distribution into tissues. The extensive work and findings with endogenous ligands suggest that FABPs may also alter the metabolism and transport of drugs. This review illustrates the potential significance of this understudied area.