The ABCG2 transporter in protoporphyrin IX disposition: from toxicity to therapy

摘要 红细胞生成性原卟啉症（EPP）和X连锁原卟啉症（XLP）是两种遗传性疾病 其特征在于原卟啉IX（PPIX）介导的光毒性和肝毒性，并且无法治愈。 本项目的目标是开发一种基于机制的策略来管理PPIX介导的 毒性我们的初步研究发现，PPIX的外排转运蛋白ABCG 2在PPIX的表达中起着重要的作用。 在PPIX介导的毒性中起作用，而ABCG 2的缺乏可消除此类毒性。我们的进一步研究 发现ABCG 2缺乏调节PPIX分布和代谢。基于这些结果，我们 假设ABCG 2抑制将通过调节PPIX而减弱PPIX介导的毒性 处分为了验证我们的假设，我们提出了以下具体目标：（1）开发ABCG 2 用于管理PPIX介导的毒性的抑制剂;（2）确定疗效、安全性和 这些新型ABCG 2抑制剂预防PPIX介导的光毒性的作用机制; 和（3）确定ABCG 2抑制剂用于治疗的功效、安全性和作用机制 PPIX介导的肝毒性。我们已经成功合成了28种ABCG 2抑制剂， 初步数据是有希望的，因为几个测试的候选物显示出强烈的ABCG 2抑制作用， 活性和对PPIX介导的毒性的巨大功效。总之，本项目将探讨 ABCG 2抑制剂用于管理PPIX介导的光毒性的治疗潜力， 肝毒性我们还将说明ABCG 2抑制减弱PPIX的机制。 介导的毒性。基因工程ABCG 2和EPP小鼠模型以及ABCG 2 在我们提出的工作中将使用抑制剂。该项目的结果将为以下方面提供一种新的战略： EPP和XLP的管理。

ABSTRACT Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are two genetic diseases characterized by protoporphyrin IX (PPIX)-mediated phototoxicity and hepatotoxicity, and there is no cure. The objective of this project is to develop a mechanism-based strategy to manage PPIX-mediated toxicities. Our preliminary studies found that ABCG2, the efflux transporter of PPIX, plays an essential role in PPIX-mediated toxicities, and deficiency of ABCG2 abolishes such toxicities. Our further studies found that ABCG2 deficiency modulates PPIX distribution and metabolism. Based on these results, we hypothesize that suppression of ABCG2 will attenuate PPIX-mediated toxicities by modulating PPIX disposition. To test our hypothesis, we propose the following specific aims: (1) to develop ABCG2 inhibitors for the management of PPIX-mediated toxicities; (2) to determine the efficacy, safety, and mechanisms of action of these novel ABCG2 inhibitors for the prevention of PPIX-mediated phototoxicity; and (3) to determine the efficacy, safety, and mechanisms of action of ABCG2 inhibitors for the treatment of PPIX-mediated hepatotoxicity. We have successfully synthesized 28 ABCG2 inhibitors, and our preliminary data are promising because several of the tested candidates showed strong ABCG2 inhibitory activity and great efficacy against PPIX-mediated toxicities. In summary, this project will explore the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated phototoxicity and hepatotoxicity. We will also illustrate the mechanisms by which suppression of ABCG2 attenuates PPIX- mediated toxicities. Genetically engineered ABCG2 and EPP mouse models together with ABCG2 inhibitors will be used in our proposed work. The results from this project will provide a novel strategy for the management of EPP and XLP.