Dell Pediatric Research Institute, University of Texas at Austin, Austin, TX, USA.
Departments of Cell Biology, 608 Stanton L, Young Blvd, Oklahoma City, OK, 73104, USA; Departments of Ophthalmology and Dean McGee Eye Institute, 608 Stanton L, Young Blvd, Oklahoma City, OK, 73104, USA; University of Oklahoma Health Sciences Center, 608 Stanton L, Young Blvd, Oklahoma City, OK, 73104, USA.
Exp Eye Res. 2022 Sep;222:109193. doi: 10.1016/j.exer.2022.109193. Epub 2022 Jul 20.
Docosahexaenoic acid (DHA; 22:6n-3) rich photoreceptors function in a highly oxidizing microenvironment. Lipid peroxidation and inflammation contribute to initiation and progression of eye diseases including age-related macular degeneration (AMD). Deuteration of DHA at the bis-allylic positions (D-DHA) increases its resilience to oxidative damage in vitro. We studied the pharmacokinetics of dietary D-DHA as a therapy for replacing natural retinal DHA in vivo. Mice were fed 0.5% D-DHA for 77 days then switched to natural DHA (H-DHA) for 74 days. Tissue were harvested for analyses at various time points. D-DHA substitution levels were 75%-80% in the CNS and above 90% in all other tissues by day 77. D-DHA accretion was rapid in plasma and liver (t ∼2.8 d), followed by heart and red blood cells (t ∼8.5 d), then ocular tissues (choroid-RPE, neural retina, and optic nerve with t of 10.1, 23.4, and 26.3 days, respectively), while CNS accretion was slowest (t of 29.0-44.3 days). D-DHA elimination rates were comparable to, or slower than, accretion rates except for optic nerve. Retina had very long chain D-PUFA (D-VLC-PUFA) with 5 and 6 double bonds up to C36, as well as D-EPA and D-DPA derived metabolically from D-DHA. The neural retina and optic nerve reached the therapeutic target window (20%-50%) in 2-4 weeks. Biosynthesis of D-VLC-PUFA is consistent with normal metabolism. D-DHA crosses the blood-retina-barrier, enters visually active tissues, and is metabolized as its natural DHA parent where, as shown previously (Liu et al., 2022), it protects against lipid peroxidation.
二十二碳六烯酸（DHA；22:6n-3）含量丰富的感光细胞在高度氧化的微环境中发挥作用。脂质过氧化和炎症导致包括年龄相关性黄斑变性（AMD）在内的眼部疾病的发生和发展。DHA 的双烯丙基位置氘化（D-DHA）可增加其在体外对氧化损伤的抵抗力。我们研究了膳食 D-DHA 作为一种替代体内天然视网膜 DHA 的治疗方法的药代动力学。将小鼠喂食 0.5%的 D-DHA 持续 77 天，然后切换到天然 DHA（H-DHA）喂养 74 天。在不同时间点采集组织进行分析。到第 77 天，CNS 中的 D-DHA 替代水平为 75%-80%，其他所有组织中的替代水平均高于 90%。D-DHA 在外周组织中的积累速度较快（t∼2.8d），随后在肝脏和心脏中（t∼8.5d），然后在眼部组织（脉络膜-RPE、神经视网膜和视神经，t 分别为 10.1、23.4 和 26.3 天），而中枢神经系统的积累速度最慢（t 为 29.0-44.3 天）。除了视神经，D-DHA 的消除率与积累率相当或更慢。视网膜具有长达 36 个碳原子的长链 D-PUFA（D-VLC-PUFA），具有 5 和 6 个双键，以及代谢产生的 D-EPA 和 D-DPA。神经视网膜和视神经在 2-4 周内达到治疗目标窗（20%-50%）。D-VLC-PUFA 的生物合成与正常代谢一致。D-DHA 穿过血视网膜屏障，进入视觉活跃组织，并被代谢为其天然 DHA 母体，正如之前（Liu 等人，2022）所示，它可以防止脂质过氧化。
