Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein (FABP1) and FABP1 Binding Alters Drug Metabolism.

Autor: Yabut KCB; Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, United States., Martynova A; Department of Chemistry, University of Washington, Seattle, WA, United States., Nath A; Department of Medicinal Chemistry, University of Washington, Seattle, WA., Zercher BP; Department of Chemistry, University of Washington, Seattle, WA, United States., Bush MF; Department of Chemistry, University of Washington, Seattle, WA, United States., Isoherranen N; Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA, United States.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 19. Date of Electronic Publication: 2024 Jan 19.
DOI: 10.1101/2024.01.17.576032
Abstrakt: Liver fatty acid binding protein (FABP1) binds diverse endogenous lipids and is highly expressed in the human liver. Binding to FABP1 alters the metabolism and homeostasis of endogenous lipids in the liver. Drugs have also been shown to bind to rat FABP1, but limited data is available for human FABP1 (hFABP1). FABP1 has a large binding pocket and multiple fatty acids can bind to FABP1 simultaneously. We hypothesized that drug binding to hFABP1 results in formation of ternary complexes and that FABP1 binding alters drug metabolism. To test these hypotheses native protein mass spectrometry (MS) and fluorescent 11-(dansylamino)undecanoic acid (DAUDA) displacement assays were used to characterize drug binding to hFABP1 and diclofenac oxidation by cytochrome P450 2C9 (CYP2C9) was studied in the presence and absence of hFABP1. DAUDA binding to hFABP1 involved high (K d,1 =0.2 µM) and low affinity (K d,2 >10 µM) binding sites. Nine drugs bound to hFABP1 with K d values ranging from 1 to 20 µM. None of the tested drugs completely displaced DAUDA from hFABP1 and fluorescence spectra showed evidence of ternary complex formation. Formation of DAUDA-diclofenac-hFABP1 ternary complex was verified with native MS. Docking placed diclofenac in the portal region of FABP1 with DAUDA in the binding cavity. Presence of hFABP1 decreased the k cat and K m,u of diclofenac with CYP2C9 by ~50% suggesting that hFABP1 binding in the liver will alter drug metabolism and clearance. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 interacts with CYP2C9.
Competing Interests: No author has an actual or perceived conflict of interest with the contents of this article.
Databáze: MEDLINE
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