Inhibitory effects of fenretinide metabolites N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR) on fenretinide molecular targets β-carotene oxygenase 1, stearoyl-CoA desaturase 1 and dihydroceramide Δ4-desaturase 1.
Inhibitory effects of fenretinide metabolites N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR) on fenretinide molecular targets β-carotene oxygenase 1, stearoyl-CoA desaturase 1 and dihydroceramide Δ4-desaturase 1.
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DOI：
10.1371/journal.pone.0176487
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Redmond TM
中科院分区：
文献类型：
--
作者：
Poliakov E;Samuel W;Duncan T;Gutierrez DB;Mata NL;Redmond TM
芬维甲酸（N-[4-羟基苯基]维甲酸；4-HPR）的治疗能力已被证明可以治疗多种疾病，包括癌症、肥胖、糖尿病和眼部疾病。然而，其多效性的作用机制仍不明确。我们假设研究芬维甲酸的两种主要生理代谢产物N-[4-甲氧基苯基]维甲酸（MPR）和4-氧-N-（4-羟基苯基）维甲酸（3-酮- hpr），可能开始解决这种合成类维甲酸的多方面影响。我们在体外分析了芬维甲酸、MPR、3-酮- hpr和非维甲酸RBP4配体A1120对芬维甲酸已知靶点、硬脂酰辅酶a去饱和酶1 （SCD1）和二氢神经酰胺Δ4-desaturase 1 （DES1）在ARPE-19细胞中的活性的影响，并纯化了重组小鼠β -胡萝卜素加氧酶1 （BCO1）。脂类和类维生素a分别采用液相色谱-质谱法和反相高效液相色谱法进行提取和定量。数据表明，虽然芬维甲酸是这三种酶活性的抑制剂，但3-酮- hpr是这三种酶的更有效抑制剂，可能介导芬维甲酸在体内的大部分有益作用。然而，尽管MPR不影响SCD1和DES1活性，但它是一种有效的BCO1特异性抑制剂。我们的结论是，对芬瑞啶及其代谢物的作用机制的深入了解为治疗特异性提供了新的途径。例如，如果目标是抑制SCD1或DES1活性（癌症），则施用3-酮- hpr而不是芬维甲酸可能更好，而MPR可能更适合BCO1调节（类胡萝卜素代谢）。在芬维甲酸各种治疗用途的背景下，对芬维甲酸代谢物的持续研究将开始解决该化合物的多效性。
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.