Cytochrome P450 1B1 and Development and Functions of Trabecular Meshwork

Cytochrome P450 1B1 (CYP1B1) belongs to the CYP450 superfamily of heme-binding monooxygenases which catalyze oxidations of various endogenous and exogenous substrates. The expression of CYP1B1 in the ocular tissues plays an important role in the modulation of development and functions of trabecular meshwork (TM). Mutation in CYP1B1 is reported in patients with primary congenital glaucoma. Mice lacking Cyp1b1 also exhibit developmental defects in TM similar to those reported in congenital glaucoma patients. However, how Cyp1b1 deficiency contributes to TM dysgenesis remains unknown.;Here we show increased diurnal intraocular pressures (IOPs) in Cyp1b1-deficient (Cyp1b1-/-) mice. Increased lipid peroxidation was detected in the TM from Cyp1b1 -/- mice. Cyp1b1-/- mice presented ultrastructural irregular collagen distribution in their TM tissues since postnatal 2 weeks, which was prevented by administration of the antioxidant N-acetylcysteine (NAC). Cyp1b1-/- TM tissues showed decreased in vivo levels of Periostin (Postn).;To gain further insight into the role CYP1B1 plays in the cellular functions in the trabecular meshwork, trabecular meshwork cells were isolated from Cyp1b1+/+ and Cyp1b1-/- mice. CYP1B1/ Cyp1b1 protein was constitutively expressed in human and mouse TM cells. Cyp1b1-/- TM cells were less viable under exogenous oxidative stress, more adherent to matrix proteins and secreted significantly decreased levels of Postn, an extracellular matrix protein essential in collagen fibrillogenesis. These aberrant cellular responses were restored in the presence of NAC or by adenoviral re-expression of Cyp1b1. Cyp1b1 knockdown or inhibition of Cyp1b1 protein activity in Cyp1b1+/+ TM cells also recapitulated a Cyp1b1 -/- phenotype.;Increased levels of oxidative stress and decreased levels of Postn were also detected in human glaucomatous TM tissues. Furthermore, Postn -deficient (Postn-/-) mice exhibited similar TM tissue ultrastructural abnormalities as Cyp1b1-/- mice. In addition, IOPs of Postn-/- mice increased as compared with wild-type control mice. These findings together suggest that metabolic activity of Cyp1b1 contributes to oxidative homeostasis and ultrastructural organization and function of TM tissues through modulation of Postn expression.