Departments of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
Department of Environmental and Molecular Toxicology, Organ State University, Corvallis, OR 97331, USA.
Cells. 2022 Sep 20;11(19):2930. doi: 10.3390/cells11192930.
Cytochrome P450 (CYP) 1B1 belongs to the superfamily of heme-containing monooxygenases. Unlike other CYP enzymes, which are highly expressed in the liver, CYP1B1 is predominantly found in extrahepatic tissues, such as the brain, and ocular tissues including retina and trabecular meshwork. CYP1B1 metabolizes exogenous chemicals such as polycyclic aromatic hydrocarbons. CYP1B1 also metabolizes endogenous bioactive compounds including estradiol and arachidonic acid. These metabolites impact various cellular and physiological processes during development and pathological processes. We previously showed that CYP1B1 deficiency mitigates ischemia-mediated retinal neovascularization and drives the trabecular meshwork dysgenesis through increased levels of oxidative stress. However, the underlying mechanisms responsible for CYP1B1-deficiency-mediated increased oxidative stress remain largely unresolved. Iron is an essential element and utilized as a cofactor in a variety of enzymes. However, excess iron promotes the production of hydroxyl radicals, lipid peroxidation, increased oxidative stress, and cell damage. The retinal endothelium is recognized as a major component of the blood-retinal barrier, which controls ocular iron levels through the modulation of proteins involved in iron regulation present in retinal endothelial cells, as well as other ocular cell types including trabecular meshwork cells. We previously showed increased levels of reactive oxygen species and lipid peroxidation in the absence of CYP1B1, and in the retinal vasculature and trabecular meshwork, which was reversed by administration of antioxidant N-acetylcysteine. Here, we review the important role CYP1B1 expression and activity play in maintaining retinal redox homeostasis through the modulation of iron levels by retinal endothelial cells. The relationship between CYP1B1 expression and activity and iron levels has not been previously delineated. We review the potential significance of CYP1B1 expression, estrogen metabolism, and hepcidin-ferroportin regulatory axis in the local regulation of ocular iron levels.
细胞色素 P450（CYP）1B1 属于血红素单加氧酶超家族。与其他在肝脏中高度表达的 CYP 酶不同，CYP1B1 主要存在于肝外组织，如脑和眼部组织，包括视网膜和小梁网。CYP1B1 代谢外源性化学物质，如多环芳烃。CYP1B1 还代谢内源性生物活性化合物，如雌二醇和花生四烯酸。这些代谢物在发育和病理过程中影响各种细胞和生理过程。我们之前的研究表明，CYP1B1 缺乏可减轻缺血介导的视网膜新生血管形成，并通过增加氧化应激水平导致小梁网发育不良。然而，导致 CYP1B1 缺乏介导的氧化应激增加的潜在机制在很大程度上仍未解决。铁是一种必需元素，作为多种酶的辅助因子使用。然而，过量的铁会促进羟基自由基的产生、脂质过氧化、氧化应激增加和细胞损伤。视网膜内皮细胞被认为是血视网膜屏障的主要组成部分，它通过调节视网膜内皮细胞中参与铁调节的蛋白质以及包括小梁网细胞在内的其他眼细胞类型来控制眼内铁水平。我们之前的研究表明，在缺乏 CYP1B1 的情况下，视网膜血管和小梁网中的活性氧和脂质过氧化水平增加，而抗氧化剂 N-乙酰半胱氨酸的给药可逆转这种情况。在这里，我们综述了 CYP1B1 表达和活性通过视网膜内皮细胞调节铁水平在维持视网膜氧化还原平衡中的重要作用。CYP1B1 表达和活性与铁水平之间的关系以前没有被描述过。我们综述了 CYP1B1 表达、雌激素代谢和铁调素-亚铁转运蛋白调节轴在局部调节眼内铁水平方面的潜在意义。
