Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein 1 (FABP1) and FABP1 Binding Alters Drug Metabolism.
Autor: | Yabut KCB; Department of Pharmaceutics, School of Pharmacy (K.C.B.Y., N.I.), Department of Chemistry (A.M., B.P.Z., M.F.B.), and Department of Medicinal Chemistry (A.N.), University of Washington, Seattle, Washington., Martynova A; Department of Pharmaceutics, School of Pharmacy (K.C.B.Y., N.I.), Department of Chemistry (A.M., B.P.Z., M.F.B.), and Department of Medicinal Chemistry (A.N.), University of Washington, Seattle, Washington., Nath A; Department of Pharmaceutics, School of Pharmacy (K.C.B.Y., N.I.), Department of Chemistry (A.M., B.P.Z., M.F.B.), and Department of Medicinal Chemistry (A.N.), University of Washington, Seattle, Washington., Zercher BP; Department of Pharmaceutics, School of Pharmacy (K.C.B.Y., N.I.), Department of Chemistry (A.M., B.P.Z., M.F.B.), and Department of Medicinal Chemistry (A.N.), University of Washington, Seattle, Washington., Bush MF; Department of Pharmaceutics, School of Pharmacy (K.C.B.Y., N.I.), Department of Chemistry (A.M., B.P.Z., M.F.B.), and Department of Medicinal Chemistry (A.N.), University of Washington, Seattle, Washington., Isoherranen N; Department of Pharmaceutics, School of Pharmacy (K.C.B.Y., N.I.), Department of Chemistry (A.M., B.P.Z., M.F.B.), and Department of Medicinal Chemistry (A.N.), University of Washington, Seattle, Washington ni2@uw.edu. |
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Jazyk: | angličtina |
Zdroj: | Molecular pharmacology [Mol Pharmacol] 2024 May 17; Vol. 105 (6), pp. 395-410. Date of Electronic Publication: 2024 May 17. |
DOI: | 10.1124/molpharm.124.000878 |
Abstrakt: | Liver fatty acid binding protein 1 (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 are available for human FABP1 (hFABP1). FABP1 has a large binding pocket, and up to two 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 (Copyright © 2024 by The Author(s).) |
Databáze: | MEDLINE |
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