The Prostaglandin Transporter OATP2A1 Is Expressed in Human Ocular Tissues and Transports the Antiglaucoma Prostanoid Latanoprost
The Prostaglandin Transporter OATP2A1 Is Expressed in Human Ocular Tissues and Transports the Antiglaucoma Prostanoid Latanoprost
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DOI：
10.1167/iovs.09-4290
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Zolk, Oliver
中科院分区：
文献类型：
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作者：
Kraft, Michaela E.;Glaeser, Hartmut;Zolk, Oliver
目的。拉坦前列素是一种前列腺素 F-2 α 类似物，已成为治疗青光眼最广泛使用的药物之一。作者假设有机阴离子转运多肽 (OATP) 负责将拉坦前列素摄取到眼组织中，因此它们导致了药物浓度和效果的个体差异。方法。使用实时 RT-PCR 和免疫荧光测定人眼组织中前列腺素 (PG) 转运蛋白（OATP2A1、OATP2B1）的表达。在过表达 OATP2A1 或 OATP2B1 的稳定转染的人胚胎肾细胞中测试了拉坦前列素及其活性代谢物（游离酸）之间的抑制相互作用以及原型底物（PGE(2) 和溴磺酞）的摄取。这些细胞还用于研究拉坦前列素和拉坦前列素酸是否是 OATP2A1 或 OATP2B1 的底物。结果。 OATP2A1 和 OATP2B1 mRNA 表达在脉络膜/视网膜色素上皮 (RPE) 复合体和睫状体中最高。 OATP2A1 蛋白表达在 RPE 以及眼前段组织（如角膜、结膜、虹膜和睫状体）的上皮细胞和内皮细胞层中最为突出，而 OATP2B1 蛋白在小梁网、施莱姆管和脉络膜血管系统中也有表达。拉坦前列素和拉坦前列素酸显着抑制 OATP2A1 和 OATP2B1。摄取实验表明，拉坦前列素酸可被 OATP2A1 有效转运（亲和常数 [K-m]，5.4 μM；最大摄取速率 [V-max]，21.5 pmol/mg 蛋白质/分钟），而 OATP2B1 转运效果较差。结论。本文呈现的结果表明至少OATP2A1在治疗用前列腺素类拉坦前列素的眼内分布中发挥作用。 （投资眼科可见科学。2010；51：2504-2511）DOI：10.1167/iovs.09-4290
PURPOSE. Latanoprost, a prostaglandin F-2 alpha analogue, has become one of the most widely used medications for the treatment of glaucoma. The authors hypothesized that organic anion transporting polypeptides (OATPs) are responsible for the uptake of latanoprost into ocular tissues and, hence, that they contribute to the interindividual differences in drug concentrations and effects.METHODS. Expression of prostaglandin (PG) transporters (OATP2A1, OATP2B1) in human ocular tissues was determined using real-time RT-PCR and immunofluorescence. The inhibitory interactions between latanoprost and its active metabolite (the free acid) and the uptake of prototypical substrates (PGE(2) and bromosulfophthalein) were tested in stably transfected human embryonic kidney cells overexpressing either OATP2A1 or OATP2B1. These cells were also used to investigate whether latanoprost and latanoprost acid are substrates of OATP2A1 or OATP2B1.RESULTS. OATP2A1 and OATP2B1 mRNA expression was highest in the choroid/retinal pigment epithelium (RPE) complex and ciliary body. OATP2A1 protein expression was most prominent in the RPE and in epithelial and endothelial cell layers of anterior segment tissues, such as cornea, conjunctiva, iris, and ciliary body, whereas OATP2B1 protein was additionally expressed in trabecular meshwork, Schlemm canal, and choroidal vasculature. Latanoprost and latanoprost acid significantly inhibited both OATP2A1 and OATP2B1. Uptake experiments demonstrated that latanoprost acid is effectively transported by OATP2A1 (affinity constant [K-m], 5.4 mu M; maximum uptake rate [V-max], 21.5 pmol/mg protein/min) and less effectively by OATP2B1.CONCLUSIONS. The results presented herein suggest that at least OATP2A1 plays a role in the intraocular disposition of the therapeutically used prostanoid latanoprost. (Invest Ophthalmol Vis Sci. 2010;51:2504-2511) DOI:10.1167/iovs.09-4290