Interaction of Cytochrome P450 3A4 with Fatty Acid Binding Protein 1 and Relevance to Drug Metabolism
Kevin D. McCarty, Destiny L. D. Proffett, F. Peter Guengerich
TL;DR
This study explores how FABP1 interacts with P450 3A4, affecting drug metabolism and potentially influencing drug effectiveness and safety.
Contribution
The study reveals FABP1's role in modulating P450 3A4 activity through substrate transfer and competition.
Findings
FABP1 binds to P450 3A4 substrates diazepam and sulfinpyrazone with high affinity.
FABP1 weakly inhibits P450 3A4 oxidation of drugs, with varying effects depending on the substrate.
Kinetic modeling suggests FABP1 may compete with P450 3A4 for drug binding at high concentrations.
Abstract
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 K d 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…
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Taxonomy
TopicsPharmacogenetics and Drug Metabolism · Peroxisome Proliferator-Activated Receptors · Eicosanoids and Hypertension Pharmacology