Interaction of Cytochrome P450 3A4 with Fatty Acid Binding Protein 1 and Relevance to Drug Metabolism

Liver fatty acid binding protein (FABP1) is an abundant
cytosolic
component that interacts with drugs and can transfer substrates to
cytochrome P450 enzymes (P450s, CYPs). FABP1 bound the P450 3A4 substrates
diazepam and sulfinpyrazone with Kd values
< 2.5 μM. FABP1 weakly attenuated P450 3A4 oxidations of
both drugs in two independent assay modes. Reconstitution of human
liver microsomes with cytosol attenuated diazepam metabolism but stimulated
sulfinpyrazone oxidation, possibly due to GST A1-1. Kinetic modeling
of reactions with varying FABP1 and substrate concentrations favored
a model of directed substrate transfer to P450 3A4. Kinetic simulations
revealed FABP1-dependent inhibition of diazepam oxidation at high
physiological concentrations of FABP1, likely due to competition for
P450 binding. Consideration of the influence of both P450 and FABP1
on drug metabolism may be critical for accurate modeling and prediction
of drug pharmacokinetics.