Challenges and Opportunities in P450 Research on the Eye

Drug Metabolism and Disposition · 1 author, 1 centre

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TL;DR

This review summarizes the expression and roles of cytochrome P450 enzymes in the eye, highlighting that at least 30 of the 57 human P450s are expressed in ocular tissues. These enzymes are involved in drug metabolism, sterol metabolism, fatty acid hydroxylation, and vitamin A metabolism, with implications for conditions like glaucoma, age-related macular degeneration, and cataracts. The paper emphasizes the need for more P450 research in ophthalmology and provides practical suggestions for initiating such studies.

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**Background:** The eye is a complex organ with over 2 million operational parts, and blindness is the most feared condition in the US adult population. Cytochrome P450 enzymes (P450s) are monooxygenases involved in various metabolic processes, but their roles in the eye are not well understood. This review provides an updated summary of P450-related research in the eye, covering expression, drug delivery, and specific P450 families.

**Methods:** The author conducted a narrative review of existing literature on P450s in the eye, including studies on expression patterns, drug metabolism, and genetic associations. The review covers multiple species (human, mouse, rat, cow, etc.) and uses data from immunohistochemistry, RT-PCR, mass spectrometry, and genetic studies.

**Key Results:** At least 30 of the 57 human P450s are expressed in the eye. These include 10 drug-metabolizing P450s (e.g., CYP1A1, CYP2D6, CYP3A4), 9 sterol-metabolizing P450s (e.g., CYP1B1, CYP27A1, CYP46A1), 6 fatty acid-hydroxylating P450s (e.g., CYP2C8, CYP4V2), 4 vitamin A-metabolizing P450s (CYP26A1, CYP26B1, CYP26C1, CYP27C1), and 1 eicosanoid-metabolizing P450 (CYP4F8). Key findings include: CYP1B1 mutations cause primary congenital glaucoma (PCG) with over 150 mutations identified; CYP27A1 deficiency leads to cerebrotendinous xanthomatosis with retinal manifestations; CYP46A1 may play a role in glaucoma and diabetic retinopathy; CYP4V2 mutations cause Bietti crystalline dystrophy (BCD); and CYP2C8 and CYP2J2 are involved in retinal neovascularization. Drug delivery to the eye is challenging: only 1% to 7% of topically administered drugs reach the aqueous humor, and only 1% to 2% of systemically administered drugs reach the vitreous cavity.

**Clinical Implications:** Understanding P450s in the eye could lead to improved drug delivery and treatment for ocular diseases. For example, CYP1B1 is a target for PCG, CYP27A1 and CYP46A1 for AMD, CYP4V2 for BCD, and CYP2C8/CYP2J2 for neovascularization. The review also highlights opportunities for P450 researchers to study cholesterol metabolism in the lens, steroidogenesis in ocular tissues, and the role of vitamin A-metabolizing P450s in vision. Practical suggestions include collaborating with ophthalmology departments and using P30 Core facilities for ocular examinations.

STUDY TYPE

narrative_review

SPECIALTY

ophthalmology

SUMMARISED BY

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ORIGINAL PAPER

PMC10506698

Challenges and Opportunities in P450 Research on the Eye

Drug Metabolism and Disposition

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ABSTRACT

Of the 57 cytochrome P450 enzymes found in humans, at least 30 have ocular tissues as an expression site. Yet knowledge of the roles of these P450s in the eye is limited, in part because only very few P450 laboratories expanded their research interests to studies of the eye. Hence the goal of this review is to bring attention of the P450 community to the eye and encourage more ocular studies. This review is also intended to be educational for eye researchers and encourage their collaborations with P450 experts. The review starts with a description of the eye, a fascinating sensory organ, and is followed by sections on ocular P450 localizations, specifics of drug delivery to the eye, and individual P450s, which are grouped and presented based on their substrate preferences. In sections describing individual P450s, available eye-relevant information is summarized and concluded by the suggestions on the opportunities in ocular studies of the discussed enzymes. Potential challenges are addressed as well. The conclusion section outlines several practical suggestions on how to initiate eye-related research. SIGNIFICANCE STATEMENT This review focuses on the cytochrome P450 enzymes in the eye to encourage their ocular investigations and collaborations between P450 and eye researchers.

CITATION EXPORT

Irina A. Pikuleva. Challenges and Opportunities in P450 Research on the Eye. Drug Metabolism and Disposition. (2023). https://doi.org/10.1124/dmd.122.001072

AUTHORS

1 · 1 CENTRES

Irina A. Pikuleva

Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio