Retina Foundation of the Southwest, Dallas, TX, 75231, USA.
Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, TX, 75080, USA; Department of Bioengineering, The University of Texas at Dallas, Richardson, TX, 75080, USA.
Free Radic Biol Med. 2020 May 20;152:386-394. doi: 10.1016/j.freeradbiomed.2020.03.024. Epub 2020 Mar 27.
Age-related macular degeneration (AMD) is one of the major causes of vision loss in the elderly in most developed countries. Among other causes, oxidative stress in the retinal pigment epithelium (RPE) has been hypothesized to be a major driving force of AMD pathology. Oxidative stress could be treated by antioxidant administration into the RPE cells. However, to achieve high in-vivo efficacy of an antioxidant, it is imperative that the agent be able to penetrate the tissues and cells. Evidence suggests that lipophilicity governs cellular penetrance. Out of many antioxidant candidates, N-acetyl-L-cysteine (a prodrug of L-cysteine) (NAC) is a potent antioxidant as the bioavailability of the parent drug, L-cysteine, determines the production of glutathione; the universal antioxidant that regulates ROS. To increase the lipophilicity, four ester derivatives of N-acetylcysteine: N-acetylcysteine methyl ester, N-acetylcysteine ethyl ester, N-acetylcysteine propyl ester, and N-acetylcysteine butyl ester were synthesized. To mimic in vitro AMD conditions, hydroquinone, a component of cigarette smoke, was used as the oxidative insult. Cytosolic and mitochondrial protection against oxidative stress were tested using cytosolic and mitochondrial specific assays. The results provide evidence that these lipophilic cysteine prodrugs provide increased protection against oxidative stress in human RPE cells compared with NAC.
年龄相关性黄斑变性（AMD）是大多数发达国家老年人视力丧失的主要原因之一。在其他原因中，视网膜色素上皮（RPE）中的氧化应激被假设为 AMD 病理学的主要驱动力。可以通过将抗氧化剂施用于 RPE 细胞来治疗氧化应激。然而，为了实现抗氧化剂在体内的高疗效，该试剂必须能够穿透组织和细胞。有证据表明，亲脂性决定细胞通透性。在许多抗氧化剂候选物中，N-乙酰-L-半胱氨酸（L-半胱氨酸的前体药物）（NAC）是一种有效的抗氧化剂，因为母体药物 L-半胱氨酸的生物利用度决定了谷胱甘肽的产生；谷胱甘肽是调节 ROS 的通用抗氧化剂。为了增加亲脂性，合成了 N-乙酰半胱氨酸的四种酯衍生物：N-乙酰半胱氨酸甲酯、N-乙酰半胱氨酸乙酯、N-乙酰半胱氨酸丙酯和 N-乙酰半胱氨酸丁酯。为了模拟体外 AMD 条件，使用了香烟烟雾的成分对苯二酚作为氧化应激。使用细胞质和线粒体特异性测定法测试了细胞质和线粒体对氧化应激的保护作用。结果表明，与 NAC 相比，这些亲脂性半胱氨酸前体药物为人类 RPE 细胞提供了对氧化应激的增强保护。
