Poliakov Eugenia, Samuel William, Duncan Todd, Gutierrez Danielle B, Mata Nathan L, Redmond T Michael
Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Acucela Inc., Seattle, Washington, United States of America.
PLoS One. 2017 Apr 27;12(4):e0176487. doi: 10.1371/journal.pone.0176487. eCollection 2017.
The therapeutic capacity of fenretinide (N-[4-hydroxyphenyl] retinamide; 4-HPR) has been demonstrated for several conditions, including cancer, obesity, diabetes, and ocular disease. Yet, the mechanisms of action for its pleiotropic effects are still undefined. We hypothesized that investigation of two of the major physiological metabolites of fenretinide, N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR), might begin to resolve the multifaceted effects of this synthetic retinoid. We analyzed the effects of fenretinide, MPR, 3-keto-HPR, and the non-retinoid RBP4 ligand A1120, on the activity of known targets of fenretinide, stearoyl-CoA desaturase 1 (SCD1) and dihydroceramide Δ4-desaturase 1 (DES1) in ARPE-19 cells, and purified recombinant mouse beta-carotene oxygenase 1 (BCO1) in vitro. Lipids and retinoids were extracted and quantified by liquid chromatography-mass spectrometry and reversed phase HPLC, respectively. The data demonstrate that while fenretinide is an inhibitor of the activities of these three enzymes, that 3-keto-HPR is a more potent inhibitor of all three enzymes, potentially mediating most of the in vivo beneficial effects of fenretinide. However, while MPR does not affect SCD1 and DES1 activity, it is a potent specific inhibitor of BCO1. We conclude that a deeper understanding of the mechanisms of action of fenretinide and its metabolites provides new avenues for therapeutic specificity. For example, administration of 3-keto-HPR instead of fenretinide may be preferential if inhibition of SCD1 or DES1 activity is the goal (cancer), while MPR may be better for BCO1 modulation (carotenoid metabolism). Continued investigation of fenretinide metabolites in the context of fenretinide's various therapeutic uses will begin to resolve the pleotropic nature of this compound.
芬维A胺（N-[4-羟基苯基]视黄酰胺；4-HPR）已被证明对多种病症具有治疗作用，包括癌症、肥胖症、糖尿病和眼部疾病。然而，其多效性作用的机制仍不明确。我们推测，对芬维A胺的两种主要生理代谢产物N-[4-甲氧基苯基]视黄酰胺（MPR）和4-氧代-N-(4-羟基苯基)视黄酰胺（3-酮基-HPR）进行研究，可能有助于揭示这种合成类视黄醇的多方面作用。我们分析了芬维A胺、MPR、3-酮基-HPR以及非类视黄醇视黄醇结合蛋白4（RBP4）配体A1120对ARPE-19细胞中芬维A胺已知靶点硬脂酰辅酶A去饱和酶1（SCD1）和二氢神经酰胺Δ4-去饱和酶1（DES1）活性的影响，以及在体外对纯化的重组小鼠β-胡萝卜素加氧酶1（BCO1）活性的影响。分别通过液相色谱-质谱联用和反相高效液相色谱法提取并定量脂质和类视黄醇。数据表明，虽然芬维A胺是这三种酶活性的抑制剂，但3-酮基-HPR对这三种酶的抑制作用更强，可能介导了芬维A胺在体内的大部分有益作用。然而，虽然MPR不影响SCD1和DES1的活性，但它是BCO1的强效特异性抑制剂。我们得出结论，深入了解芬维A胺及其代谢产物的作用机制为治疗特异性提供了新途径。例如，如果目标是抑制SCD1或DES1活性（癌症），那么给予3-酮基-HPR而非芬维A胺可能更具优势，而MPR可能更适合调节BCO1（类胡萝卜素代谢）。在芬维A胺的各种治疗用途背景下继续研究其代谢产物，将有助于揭示该化合物的多效性本质。
