<br>药物与人肝脂肪酸结合蛋白 1 （FABP1）形成三元复合物，FABP1 结合改变药物代谢,Molecular Pharmacology

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药物与人肝脂肪酸结合蛋白 1 （FABP1）形成三元复合物，FABP1 结合改变药物代谢
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2024-06-01 , DOI: 10.1124/molpharm.124.000878
King Clyde B Yabut ₁ , Alice Martynova ₁ , Abhinav Nath ₁ , Benjamin P Zercher ₁ , Matthew F Bush ₁ , Nina Isoherranen ₂

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肝脏脂肪酸结合蛋白 1 （FABP1）结合多种内源性脂质，并在人肝脏中高度表达。与 FABP1 结合会改变肝脏中内源性脂质的代谢和稳态。药物也被证明与大鼠 FABP1 结合，但人 FABP1 （hFABP1）的数据有限。FABP1 有一个大的结合口袋，最多两种脂肪酸可以同时与 FABP1 结合。我们假设药物与 hFABP1 结合导致三元复合物的形成，并且 FABP1 结合会改变药物代谢。为了检验这些假设，使用天然蛋白质质谱（MS）和荧光 11-（丹酰氨基）十一酸（DAUDA）置换测定来表征药物与 hFABP1 的结合，并在存在和不存在 hFABP1 的情况下研究细胞色素 P450 2C9 （CYP2C9）的双氯芬酸氧化。DAUDA 与 hFABP1 的结合涉及高（K_d，1 = 0.2 μM）和低（K_d，2 > 10 μM）亲和力结合位点。9 种与 hFABP1 结合的药物，平衡解离常数（K_d）值范围为 1 至 20 μM。没有一种测试药物完全取代 DAUDA 与 hFABP1，荧光光谱显示三元复合物形成的证据。DAUDA-hFABP1-双氯芬酸三元复合物的形成用天然 MS 验证。对接预测了 FABP1 门区域中的双氯芬酸结合与结合腔中的 DAUDA 结合。在 FABP1 存在下，CYP2C9 对双氯芬酸羟基化的催化速率常数降低了 ∼50% （P < 0.01）。总之，这些结果表明药物与 hFABP1 形成三元复合物，并且 hFABP1 在肝脏中的结合会改变药物代谢和清除。

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Drugs Form Ternary Complexes with Human Liver Fatty Acid Binding Protein 1 (FABP1) and FABP1 Binding Alters Drug Metabolism

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_d,1 = 0.2 μM) and low (K_d,2 > 10 μM) affinity binding sites. Nine drugs bound to hFABP1 with equilibrium dissociation constant (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-hFABP1-diclofenac ternary complex was verified with native MS. Docking predicted diclofenac binding in the portal region of FABP1 with DAUDA in the binding cavity. The catalytic rate constant of diclofenac hydroxylation by CYP2C9 was decreased by ∼50% (P < 0.01) in the presence of FABP1. Together, these results suggest that drugs form ternary complexes with hFABP1 and that hFABP1 binding in the liver will alter drug metabolism and clearance.

更新日期：2024-05-18

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