CYP1B1: A key regulator of redox homeostasis

Abstract

CYP1B1 is a member of the CYP1 subfamily of CYP superfamily of enzymes, which contains three members, CYP1A1, CYP1A2, and CYP1B1. CYP1B1 is expressed in both adult and fetal human extrahepatic tissues, including the parenchymal and stromal cells of most organs. Mutations in the CYP1B1 gene are linked to the development of primary congenital glaucoma in humans. However, the underlying mechanisms remain unknown. Using Cyp1b1-deficient mice, we showed that CYP1B1 is constitutively expressed in retinal vascular cells with a significant role in retinal neovascularization during oxygen-induced ischemic retinopathy. We also showed CYP1B1 is constitutively expressed in trabecular meshwork (TM) cells and its expression plays a significant role in the normal development and function of the TM tissue. We have observed that germline deletion of Cyp1b1 is associated with increased oxidative stress in the retinal vascular and TM cells in culture, and retinal and TM tissue in vivo. We showed increased oxidative stress was responsible for altered production of the extracellular matrix proteins and had a significant impact on cellular integrity and function of these tissues. Collectively, our studies have established an important role for CYP1B1 expression in modulation of tissue integrity and function through the regulation of cellular redox homeostasis and extracellular microenvironment.

Keywords: Cytochrome P450; angiogenesis; extracellular matrix Proteins; glaucoma; oxidative stress; periostin; thrombospondin.

Figure 1.

Regulation of CYP1B1 expression, metabolic activity, and biological functions.

Figure 2.

CYP1B1 regulation of intracellular iron levels through BMP6 signaling and hepcidin production, and regulation of redox homeostasis.