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CYP1B1 substrates include exogenous aromatic hydrocarbons, such as dioxins, and endogenous bioactive compounds, including 17\u03b2-estradiol (E2) and arachidonic acid. The endogenous compounds and their metabolites are mediators of various cellular and physiological processes, suggesting that CYP1B1 activity is likely important in maintaining proper cellular and tissue functions. We previously demonstrated that lack of CYP1B1 expression and activity are associated with increased levels of reactive oxygen species and oxidative stress in the retinal vasculature and vascular cells, including retinal endothelial cells (ECs). However, the detailed mechanism(s) of how CYP1B1 activity modulates redox homeostasis remained unknown. We hypothesized that CYP1B1 metabolism of E2 affects bone morphogenic protein 6 (BMP6)-hepcidin-mediated iron homeostasis and lipid peroxidation impacting cellular redox state. Here, we demonstrate retinal EC prepared from Cyp1b1-deficient (Cyp1b1\u2212\/\u2212) mice exhibits increased estrogen receptor-\u03b1 (ER\u03b1) activity and expresses higher levels of BMP6. BMP6 is an inducer of the iron-regulatory hormone hepcidin in the endothelium. Increased hepcidin expression in Cyp1b1\u2212\/\u2212 retinal EC resulted in decreased levels of the iron exporter protein ferroportin and, as a result, increased intracellular iron accumulation. Removal of excess iron or antagonism of ER\u03b1 in Cyp1b1\u2212\/\u2212 retinal EC was sufficient to mitigate increased lipid peroxidation and reduce oxidative stress. Suppression of lipid peroxidation and antagonism of ER\u03b1 also restored ischemia-mediated retinal neovascularization in Cyp1b1\u2212\/\u2212 mice. Thus, CYP1B1 expression in retinal EC is important in the regulation of intracellular iron levels, with a significant impact on ocular redox homeostasis and oxidative stress through modulation of the ER\u03b1\/BMP6\/hepcidin axis.<\/jats:p>","DOI":"10.3390\/ijms24032420","type":"journal-article","created":{"date-parts":[[2023,1,27]],"date-time":"2023-01-27T01:58:59Z","timestamp":1674784739000},"page":"2420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cytochrome P450 1B1 Expression Regulates Intracellular Iron Levels and Oxidative Stress in the Retinal Endothelium"],"prefix":"10.3390","volume":"24","author":[{"given":"Yong-Seok","family":"Song","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail S.","family":"Zaitoun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoujian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soesiawati R.","family":"Darjatmoko","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M.","family":"Sorenson","sequence":"additional","affiliation":[{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2723-9217","authenticated-orcid":false,"given":"Nader","family":"Sheibani","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"McPherson Eye Research Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. 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