Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
Department of Radiology, School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan.
Sci Rep. 2020 Oct 5;10(1):16489. doi: 10.1038/s41598-020-73336-1.
Redox status influences the course of the inflammatory, metabolic, and proliferative liver diseases. Oxidative stress is thought to play a crucial and sustained role in the pathological progression of early steatosis to severe hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Oxidative stress induced by reactive oxygen species which are generated in the mitochondria can lead to chronic organelle damage in hepatocytes. Currently, the diagnosis of liver disease requires liver biopsy, which is invasive and associated with complications. The present report describes the development of a novel molecular probe, EDA-PROXYL, with higher reactivity and mitochondrial selectivity than standard carboxyl-PROXYL and carbamoyl-PROXYL probes. The membrane permeability of our probe improved in aqueous environments which led to increased accumulation in the liver and interaction of EDA-PROXYL with the carnitine transporter via the amine (NH) group further increased accumulation. This increased mitochondrial sensitivity and enhanced accumulation highlight the potential of EDA-PROXYL as a molecular probe for determining metabolic reactions of the mitochondria. Thus, this novel probe could be a tool for the evaluation of redox status of the mitochondria to assess the degree of liver injury and, ultimately, the response to pharmacological therapy.
氧化还原状态影响炎症、代谢和增殖性肝病的进程。氧化应激被认为在早期脂肪变性向严重肝炎、纤维化、肝硬化和肝细胞癌的病理进展中起着关键和持续的作用。活性氧（ROS）在线粒体中产生，导致肝细胞的慢性细胞器损伤。目前，肝脏疾病的诊断需要进行肝活检，这是一种有创的检查，并且会伴有并发症。本报告介绍了一种新型分子探针 EDA-PROXYL 的开发，与标准的羧基-PROXYL 和氨甲酰基-PROXYL 探针相比，该探针具有更高的反应性和线粒体选择性。我们的探针在水相环境中的膜通透性提高，导致在肝脏中的积累增加，并且通过胺（NH）基团与肉碱转运蛋白的相互作用进一步增加了积累。这种增加的线粒体敏感性和增强的积累突出了 EDA-PROXYL 作为线粒体代谢反应的分子探针的潜力。因此，这种新型探针可以作为评估线粒体氧化还原状态的工具，以评估肝损伤的程度，并最终评估对药物治疗的反应。
